The rising incidence of nonalcoholic fatty liver disease (NAFLD) poses a great socioeconomic burden worldwide. Also, periodontitis is the most common chronic inflammatory disease caused by a group of oral pathogens, affecting both oral health and systemic conditions, especially liver disease. Although accumulating evidence has elucidated an association between periodontal pathogens and NAFLD, the role of periodontal pathogen-derived outer membrane vesicles (OMVs) has not yet been clarified. In this comprehensive review, we aim to address this gap by summarising the progression and pathogenesis of NAFLD and revealing the relationship between periodontal disease and NAFLD multidimensionally. Additionally, this review sheds light on the multifunctional roles of periodontal pathogens OMVs and emphasises that periodontal pathogen-derived OMVs promote the development of NAFLD by stimulating Kupffer cells to produce inflammatory factors and inducing the activation of Hepatic stellate cells. However, it is still controversial whether periodontal pathogen-derived OMVs can be transferred to the liver through the bloodstream route or the oral-gut-liver axis. This highlights the pressing need for continued research efforts to develop new and optimised research schemes to observe the formation of the systemic distribution pathway of periodontal pathogen-derived OMVs. Finally, it is notable that there are currently no relevant clinical treatment guidelines to make specific provisions on controlling the level of periodontal pathogen-derived OMVs in patients with NAFLD. Guidelines developed based on our findings may contribute to the standardisation of practices. It can also provide effective strategies and potential therapeutic targets for NAFLD patients with periodontitis to alleviate the development of NAFLD diseases by inhibiting periodontal pathogens OMVs.

Recently, the term Metabolic-Associated Fatty Liver Disease (MAFLD) has been adopted to better reflect the underlying pathology and association with metabolic issues. Beyond dietary factors and physical activity, previous studies have suggested that persistent organic pollutants (POPs) may contribute to the etiology of MAFLD; however, this disease can also develop at very low POP exposure levels, making it challenging to discern their specific effect. This study aims to investigate the potential link between exposure to POPs and the prevalence of MAFLD. Data from the National Health and Nutrition Examination Survey (NHANES) was utilized for this cross-sectional study. Participants were categorized based on their MAFLD status and levels of various POPs measured in their blood serum. Cox regression to estimate adjusted prevalence ratio (aPR) of MAFLD was used. Hazard Index (HI), Proportion of Maximum Scaling (POMS), and Toxicity Burden Index (TBI) were applied to assess exposure to mixtures. A total of 4,224 participants were included, 47 (33-65) years, 53.0% were women, and 50.1% had MAFLD. No significant sex differences were observed in the main analysis regarding the association between individual POPs and MAFLD prevalence. However, sensitivity analyses revealed an inverse relationship between certain POPs and MAFLD prevalence, particularly in women. Higher levels of specific PCBs were associated with a lower prevalence of MAFLD in women. This study highlighted the effects of individual pollutants, mixtures, and sex-specific differences. The combined use of HI, POMS, and TBI provided a more detailed risk assessment. Findings suggest that biological sex and metabolic stressors play significant roles in how POPs influence MAFLD, warranting further investigation into mechanisms and health outcomes in different exposure ranges.

In 2023, metabolic dysfunction-associated steatotic liver disease (MASLD) was introduced following metabolic dysfunction-associated fatty liver disease (MAFLD). Both aim to address the limitations of nonalcoholic fatty liver disease (NAFLD). This review analyzes the similarities and differences between MAFLD and MASLD, focusing on their impacts on epidemiology, diagnosis, stigma, and related liver diseases.

Current evidence suggests that MAFLD criteria effectively identify individuals at higher risk through a good balance of sensitivity and specificity. Moreover, MAFLD is a more generalizable term that is easily understood globally.

The transition from NAFLD to MAFLD and MASLD marks a significant advance in understanding fatty liver disease within hepatology. MAFLD identifies a homogeneous cohort of patients with fatty liver due to metabolic dysfunction and provides a valuable framework for holistic, patient-centered management strategies that consider various contributing factors to improve health outcomes.

The advanced lung cancer inflammation index (ALI) is a composite index that combines inflammation and nutritional status, and non-alcoholic fatty liver disease (NAFLD) is associated with inflammation, nutritional status, and obesity. This study aimed to investigate the possible relationship between ALI and NAFLD.

We extracted cohort datasets from the 2017-2020 National Health and Nutrition Examination Survey (NHANES) for the study. Weighted analyses and multivariate linear regression models were applied to assess the association between ALI and NAFLD. Fitted curves and threshold effects analyses were used to characterize nonlinear relationships.

A total of 6,595 adults aged 18-80 years were included in this study. In multivariate linear regression analysis, there was a significant positive association between ALI and NAFLD [OR: 1.02, 95% CI (1.01, 1.02)]. In subgroup analyses, this positive association was maintained in females [OR: 1.02, 95% CI (1.01, 1.02)] and not in males. In addition, we found that the association between ALI and NAFLD was nonlinear, with an L-shaped relationship and an inflection point of 32.47. ALI showed a U-shaped association with NAFLD in the male population, with an inflection point of 40.65, and an L-shaped association in the female population, with an inflection point of 30.61.

Our study suggests that there is a significant positive association between high ALI levels and NAFLD prevalence in the US adult population. However, more clinical cohort studies are needed to confirm this finding.

Metabolic syndrome (MetS) and metabolic dysfunction-associated steatotic liver disease (MASLD) are closely related, with rapidly increasing prevalence globally, driving significant public health concerns. Both conditions share common pathophysiological mechanisms such as insulin resistance (IR), adipose tissue dysfunction, oxidative stress, and gut microbiota dysbiosis, which contribute to their co-occurrence and progression. While the clinical implications of this overlap, including increased cardiovascular, renal, and hepatic risk, are well recognized, current diagnostic and therapeutic approaches remain insufficient due to the clinical and individuals' heterogeneity and complexity of these diseases. This review aims to provide an in-depth exploration of the molecular mechanisms linking MetS and MASLD, identify critical gaps in our understanding, and highlight existing challenges in early detection and treatment. Despite advancements in biomarkers and therapeutic interventions, the need for a comprehensive, integrated approach remains. The review also discusses emerging therapies targeting specific pathways, the potential of precision medicine, and the growing role of artificial intelligence in enhancing research and clinical management. Future research is urgently needed to combine multi-omics data, precision medicine, and novel biomarkers to better understand the complex interactions between MetS and MASLD. Collaborative, multidisciplinary efforts are essential to develop more effective diagnostic tools and therapies to address these diseases on a global scale.

Prior work has shown that MRI-derived proton density fat fraction (PDFF) can diagnose metabolic dysfunction-associated steatotic liver disease (MASLD) noninvasively, but there is a paucity of data on the performance of PDFF to classify more advanced forms of the MASLD spectrum. The purpose of this study was to assess the diagnostic performance of PDFF for the diagnoses of MASLD, metabolic dysfunction-associated steatohepatitis (MASH), and fibrotic MASH in adults with obesity undergoing bariatric surgery, using contemporaneous intraoperative liver biopsy as a reference.

PDFF was evaluated alone and with other potential classifiers (imaging, serum and anthropometric), using Bayesian Information Criterion-based stepwise logistic regression models. Areas under the receiver operating characteristic (ROC) curves (AUC) were computed for all models and single classifiers. Cross-validated sensitivity and specificity were calculated at Youden-based PDFF classification thresholds. Data analysis from 140 patients demonstrated that PDFF was the most accurate single classifier, with high AUC for MASLD (0.95), MASH (0.85), and fibrotic MASH (0.82) (all p <0.001). Multivariable models, including PDFF, outperformed those without PDFF. The Youden-based threshold for PDFF was 4.4% for MASLD (sensitivity: 87%, specificity: 86%), 6.9% for MASH (sensitivity: 77%, specificity: 66%), and 13.5% for fibrotic MASH (sensitivity: 67%, specificity: 85%).

PDFF was the most accurate single classifier for diagnosing MASLD, MASH, and fibrotic MASH. The most accurate multivariable classification models for MASLD, MASH, and fibrotic MASH included PDFF, demonstrating the central importance of PDFF for noninvasive assessment of the MASLD spectrum.

Background: Triglyceride glucose (TyG) and its related index (TyG-body mass index, TyG-BMI) are recognized as markers for nonalcoholic fatty liver disease (NAFLD), but their associations with metabolic dysfunction-associated steatotic liver disease (MASLD) and significant liver fibrosis (SLF) risk are less studied. Therefore, this study explores the effectiveness of these indices in assessing MASLD and SLF risk in the U.S. population. Methods: Utilizing data from the National Health and Nutrition Examination Survey (NHANES), a cross-sectional study involving 5520 participants from the general population was performed. This research measured demographic, anthropometric, biochemical, comorbid, and lifestyle characteristics, all of which are considered risk factors for MASLD/SLF. Results: Upon controlling for confounding variables, only the TyG-BMI was found to have a consistent positive association with the risk of MASLD and SLF. Specifically, for each standard deviation increase, the odds ratio (OR) and 95% confidence interval (CI) were 4.44 (3.64-9.26, p for trend < 0.001) for MASLD and 2.48 (2.15-2.87, p for trend < 0.001) for SLF. Significant interactions were identified among age, sex, and the risk of MASLD associated with the TyG-BMI. The TyG-BMI also had a significant threshold effect on the risk of MASLD at a cutoff point of 180.71. Furthermore, the area under the receiver operating characteristic curve (AUC) revealed that the TyG-BMI better predicted the risk of MASLD and SLF (AUC 0.820, 95% CI 0.810-0.831; AUC 0.729, 95% CI 0.703-0.756, respectively). In addition, the integrated discrimination improvement (IDI), decision curve analysis (DCA), and net reclassification index (NRI) also demonstrated the satisfactory predictive ability of the TyG-BMI. Conclusions: Within this large dataset, the TyG-BMI was independently associated with both the MASLD score and the SLF in the MASLD cohort. Its predictive efficacy consistently surpassed that of TyG and other noninvasive models, indicating that TyG-BMI has potential for the early identification of MASLD and SLF risk.

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.

Background: The prevalence of fatty liver disease in people living with human immunodeficiency virus (PLHIV) is significantly higher than in general population. This study aims to compare the burden of fatty liver disease in Egyptian PLHIV using both metabolic dysfunction-associated fatty liver disease (MAFLD) and steatotic liver disease (SLD) criteria. Methods: A retrospective cross-sectional study was conducted on PLHIV attending the HIV reference center at Embaba Fever Hospital in Egypt between November 2019 and July 2021. Data collection included demographics, comorbidities, physical examination, laboratory tests, liver ultrasound, controlled attenuation parameter, and liver stiffness measurement using Fibroscan®. Results: The prevalence of SLD and MAFLD was 26.92% and 21.15%, respectively. The concordance between MAFLD and SLD definitions was low (kappa = 0.465). The presence of SLD was significantly associated with increased odds of significant fibrosis (P = 0.045). However, MAFLD was not significantly associated with fibrosis (P = 0.369). Conclusion: SLD demonstrates a stronger association with significant fibrosis than MAFLD in PLHIV. This highlights the potential of SLD as a more inclusive and representative classification for steatosis in PLHIV.

Whether the new standard of metabolic dysfunction-associated fatty liver disease (MAFLD) has more pronounced clinical and population screening diagnostic value than nonalcoholic fatty liver disease (NAFLD) is unclear. This study evaluated the utility of MAFLD and NAFLD for predicting major cardiovascular disease (CVD) risk.

A prospective cohort study approach was utilized to collect 19,399 study participants without CVD at baseline who completed follow-up from the Jinchang cohort platform during 2011-2017. According to clinical ultrasonic diagnosis results and disease diagnosis criteria, the baseline population was divided into MAFLD, NAFLD, Both-FLD and No-FLD groups. Based on the multifactorial Cox proportional risk model to analyze the relationship between three kinds of patients and CVD, the score prediction model of CVD was constructed with reference to the Framingham Risk Score (FRS) and the model was evaluated. Compared with No-FLD, the HRs and 95 % CIs for the risk of CVD development in patients with NAFLD, MAFLD, and Both-FLD were 1.54 (1.34-1.76), 1.57 (1.37-1.79), and 1.62 (1.41-1.87), in that order. The scoring model showed a range of 5.90%-84.59 % risk of CVD in the three groups. As the risk score increased, the risk of developing CVD gradually increased. Evaluation metrics of all three models in the training set and validation set showed that the models have good prediction efficacy.

In terms of CVD risk and prognosis, MAFLD had no advantage over NAFLD. However, Both-FLD was found to predict a higher risk of CVD and to have superior predictive efficacy.

The new nomenclature for metabolic dysfunction-associated steatohepatitis (MASH) requires presence of steatohepatitis in the context of at least one cardiometabolic risk. Having a health-related quality of life (HRQL) instrument validated specifically in patients with MASH is important for clinical research and clinical trials.

From our non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH) database, patients who met the definition of MASH according to the new criteria were selected. Subjects had completed the Chronic Liver Disease Questionnaire for NAFLD/NASH (CLDQ-NAFLD/NASH) and other HRQL instruments (Functional Assessment of Chronic Illness Therapy - Fatigue [FACIT-F], Short-Form 36 [SF-36]), and had available clinico-laboratory data including fibrosis non-invasive tests (NITs). The CLDQ-MASH was developed following a standard pipeline and subsequently validated in a non-overlapping sample.

There were 4,213 MASH patients included: age 56 ± 11 years, 44% male, 65% type 2 diabetes, 69% advanced fibrosis (F3-F4). The patients with MASH were split 1:2 into a training set used for development of CLDQ-MASH and a testing set used for validation using standard pipeline. After item reduction and exploratory factor analysis with the training set (>90% variance), the CLDQ-MASH contained 35 items and seven domains. With the non-overlapping testing set, CLDQ-MASH demonstrated excellent face validity, internal consistency (all Cronbach's alpha >0.78), and high correlations with relevant domains of SF-36, FACIT-F (p <0.01). Known-groups validity assessment confirmed that CLDQ-MASH can discriminate patients based on liver disease severity (histology- and NIT-based) and the presence of non-hepatic comorbidities (obesity, type 2 diabetes, depression, clinically overt fatigue, insomnia). In a subsample of subjects with 1-year follow-up, the instrument was responsive to changes in Enhanced Liver Fibrosis® scores and liver stiffness measurements (p <0.05 for four to six domains).

The CLDQ-MASH can be used as a valid disease-specific HRQL instrument for patients with MASH.

The new criteria for metabolic dysfunction-associated steatohepatitis (MASH) are different from those previously used for non-alcoholic steatohepatitis so the evidence collected for the previous criteria need to be revisited, including disease-specific instruments for assessment of health-related quality of life. In patients with MASH, Chronic Liver Disease Questionnaire-MASH (CLDQ-MASH; 35 items, seven domains) has excellent psychometric properties including its internal consistency and various aspects of validity, and is responsive to changes in liver disease severity indicators. The CLDQ-MASH can be used as a valid disease-specific health-related quality of life instrument for MASH in clinical research and clinical trials.

Little is known about the associations of changes in drinking levels with the newly defined metabolic dysfunction-associated steatotic liver disease (MASLD). We therefore sought to estimate the associations between changes in drinking levels and MASLD in less developed regions of China.

This longitudinal study included 8727 participants from the China Multi-Ethnic Cohort (CMEC) in less developed regions, all participating in baseline and a follow-up survey. MASLD was defined as hepatic steatosis, along with the presence of at least one of five cardiometabolic risks, in addition to limiting excessive alcohol consumption. We applied the parametric g-formula to evaluate the association between changes in drinking levels and MASLD. We further estimated the association between changes in drinking levels and fibrosis scores (AST-to-platelet ratio and fibrosis-4 index) in patients with MASLD.

Compared with sustained non-drinking, sustained modest drinking was associated with a higher risk of MASLD (Mean Ratio (MR): 1.127 [95% CI: 1.040-1.242]). Compared to sustained non-drinking, the MR for those transitioning from non-drinking to modest drinking was 1.065 [95% CI: 0.983-1.169], while the MR for those changing from modest drinking to non-drinking was 1.059 [95% CI: 0.965, 1.173]. Non-invasive fibrosis scores tended to increase with modest drinking compared to sustained non-drinking.

In the less developed regions of China, sustained moderate drinking was associated with the risk of MASLD compared with sustained non-drinking. Increased drinking showed a trend towards a higher risk of MASLD. This study can inform drinking policies related to MASLD and liver fibrosis in less developed regions.

The relationship between vascular endothelial function and bone mineral density (BMD) in T2DM patients with metabolic dysfunction associated fatty liver (MAFLD) is still unclear. This study aims to analyse the correlation between vascular endothelial function and BMD or fracture risk in T2DM patients with MAFLD.

A total of 872 T2DM patients aged ≥50 years were enrolled and divided into two groups according to the diagnostic criteria of MAFLD: MAFLD (+) and MAFLD (-). Flow-mediated dilation (FMD) was measured by high-resolution ultrasound to reflect vascular endothelial function. BMD was measured by dual-energy X-ray bone densitometry, and FRAX scores were calculated for 10-year hip fracture risk (HF1) and major osteoporotic fracture risk (MOF).

After multivariate adjustment, there was no significant correlation between FMD and BMD in MAFLD (-) group (p > 0.05). In MAFLD (+) and FMD < 4% group, FMD was positively correlated with WB, LS, and FN BMD, while FMD was negatively correlated with fracture risk and osteoporotic fracture history, and this correlation was only observed in female patients. However, FMD was not correlated with BMD and fracture risk and osteoporotic fracture history in 4%≤FMD ≤ 7% and FMD > 7% groups.

The association of FMD with BMD in T2DM patients with MAFLD varies according to FMD level. The decrease of FMD is associated with reduced BMD and increased fracture risk in female patients with FMD < 4% group. FMD may be an influential factor for the occurrence and development of osteoporosis, and has some clinical value in early diagnosis of osteoporosis in T2DM patients with MAFLD.

Zexie-Baizhu Decoction (AA), a Chinese Classical Formula composed of Alisma orientalis (Sam.) Juzep. and Aractylodes Macrocephala Koidz in the specific ratio of 5:2, has a long history of use in treating metabolic disorders. Recent studies have demonstrated AA's ameliorative effects on non-alcoholic fatty liver disease (NAFLD); however, the mechanism underlying its action on the gut and adipose tissue, key regulators of metabolism, have not been fully explored.

This study aimed to investigate the mechanisms by which AA regulates the homeostasis of gut and adipose tissue in NAFLD.

AA (1500 mg/kg/day) or vehicle was administrated to the high-fat diet-induced and normal chow-fed mice (C57BL/6J). Plasma, the liver, gut microbiota, bile acids, and short-chain fatty acids in the gut, were systematically investigated. RNA sequencing analysis, reverse transcription quantitative real-time PCR, and Western Blotting were performed on the epididymal white adipose tissues (eWAT) to explore AA's influence on NAFLD. Lipidomics of the liver and eWAT were analyzed by liquid chromatography-mass spectrometry and desorption electrospray ionization mass spectrometry imaging.

Our study demonstrated that AA administration effectively alleviated liver injury induced by NAFLD, as evidenced by reduced hepatic fat accumulation and inflammation. Mechanistically, AA modulated the composition of the gut microbiota, promoting the growth of beneficial bacteria such as Akkermansia muciniphila and restoring the balance between Firmicutes and Bacteroidetes. Furthermore, AA regulated the levels of bile acids and short-chain fatty acids in the intestine, plasma, and liver. Correspondingly in the eWAT, AA administration activated bile acid receptor (Gpbar1) and short-chain fatty acid receptor (Ffar2), facilitating lipid breakdown and attenuating triglyceride accumulation. Transcriptome analysis revealed that AA influenced gene expression related to fatty acid metabolism, thermogenesis, insulin resistance, AMPK signaling, and the tricarboxylic acid (TCA) cycle, thereby improving NAFLD at the transcriptional level. Additionally, AA treatment significantly altered the lipid composition in the liver, reducing levels of diacylglycerols, triacylglycerols, phosphatidylserines, and cholesterol esters, while increasing levels of phosphatidic acids, phosphatidylethanolamines, and sphingomyelins.

Our study builds a connection between the gut and adipose tissue to understand the mechanism of AA on alleviating NAFLD, providing new insights into the development of targeted therapies for this condition.

A new term, metabolic dysfunction-associated steatotic liver disease (MASLD), has been proposed by a multi-society expert panel. However, it remains unclear whether hepatic steatosis per se in MASLD contributes to an increased risk of mortality in individuals with any cardio-metabolic risk factor (CMRF), which is also a significant risk factor for increased mortality. This study aimed to compare all-cause and cause-specific mortality between the "MASLD/MetALD" and "no steatotic liver disease (SLD)" groups in individuals with any CMRF.

A population-based cohort study was conducted using 10,750 participants of the Third National Health and Nutrition Examination Survey. All-cause and cause-specific (cardiovascular, cancer, diabetes, and liver) mortality risks were compared between the "MASLD," "MetALD," and "no SLD" groups using the Cox proportional hazards model with complex survey design weights, adjusted for confounders. Over 26 years, the "MASLD" group did not show significantly increased all-cause (adjusted HR 1.04[95% CI: 0.95-1.14], p = 0.413), cardiovascular (0.88 [0.75-1.04], p = 0.139), or cancer (1.06[0.84-1.33], p = 0.635) mortality risk compared to the "no SLD" group in individuals with any CMRF. The MetALD group was associated with increased all-cause (1.41 [1.05-1.89], p = 0.022), cancer (2.35 [1.33-4.16], p = 0.004), and liver (15.04 [2.96-76.35], p = 0.002) mortality risk compared with the no SLD group. This trend was more pronounced in the MetALD group with advanced fibrosis assessed by Fibrosis-4 (FIB-4).

In individuals with CMRF, the presence of steatotic liver disease (MASLD) alone did not increase the risk of mortality, except in cases with more alcohol consumption (MetALD). Therefore controlling metabolic risk factors and reducing alcohol consumption in people with MASLD or MetALD will be crucial steps to improve long-term health outcomes.

The new nomenclature of metabolic dysfunction-associated steatotic liver disease (MASLD) substituting nonalcoholic fatty liver disease was proposed along with a new category of MASLD with increased alcohol intake (MetALD).

We aimed to explore the cancer risk by MASLD and MetALD.

This nationwide cohort study included 3,596,709 participants who underwent a health check-up in 2011 in South Korea. Steatotic liver disease (SLD) was defined as a fatty liver index ≥30. Participants were categorized into four exclusive groups: MASLD, MetALD, other combination aetiology and no SLD. The subdistribution hazard ratio (SHR) was calculated using the Fine-Gray model after adjusting other variables.

During the 33.9 million person-years of follow-up, 285,845 participants (7.9%) developed cancers. Compared with no SLD, MASLD, MetALD and other combination aetiology had an increased risk of all cancer. Liver cancer risk escalated from no SLD to MASLD (SHR, 1.16; 95% CI, 1.12-1.21), MetALD (SHR, 2.06; 95% CI, 1.92-2.20) and other combination aetiology (SHR, 8.16; 95% CI, 7.69-8.67). Gastrointestinal cancers including oesophagus, stomach, colorectal, biliary and pancreas cancers increased in MASLD (SHR, 1.13; 95% CI, 1.11-1.15), MetALD (SHR, 1.17; 95% CI, 1.14-1.21) and other combination aetiology (SHR, 1.09; 95% CI, 1.05-1.13). A modest increase in lung cancer and hormone-sensitive cancer was observed with MASLD.

This study showed that MASLD and MetALD are associated with an increased risk of cancer, particularly liver and gastrointestinal cancers. The findings build new evidence for the clinical outcomes of MetALD while highlighting the importance of managing alcohol intake properly in MASLD and MetALD.

The international consensus to revise non-alcoholic fatty liver disease to metabolic (dysfunction)-associated fatty liver disease (MAFLD) in 2020 attracted significant attention. The impact of the MAFLD definition on the research community has not been objectively assessed. We conducted an analysis of systematically collected literature on MAFLD to understand its research impact.

From PubMed, Web of Science, and Scopus, the literature adopting MAFLD, written in English, and published from 2020 to 10 October 2023 was collected. The publication metrics, including publication counts, publishing journals, author countries, author keywords, and citation information, were analyzed to evaluate the research impact and key topics on MAFLD.

1469 MAFLD-related papers were published in 434 journals with a steady increase in the number. The intense publishing and citations activity on MAFLD indicates the large impact of the redefinition. Topic assessment with keyword and citation analysis revealed a transition from the proposal and discussion of the redefinition to clinical characterization of MAFLD with a focus on metabolic dysfunction. Moreover, the diagnostic criteria for MAFLD showed better performance in predicting hepatic and extrahepatic outcomes compared to NAFLD. The publications were from 99 countries with evidence of strong regional and global collaboration. Multiple international societies and stakeholders have endorsed MAFLD for its utility in clinical practice, improving patient management and promoting multidisciplinary care, while alleviating stigma.

This survey provides a quantitative measure of the considerable international impact and contributions of the MAFLD definition towards liver research and as part of the spectrum of cardiometabolic disorders.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is now the most prevalent chronic liver disease in children in industrialized countries mainly due to the rise in obesity and overweight. Besides risk of progressive liver damage, MASLD also carries an increased risk of extra-hepatic morbidity, most importantly type 2 diabetes mellitus and cardiovascular disease. Important challenges remain in the prevention, detection, and treatment of this prevalent disorder. This review outlines the epidemiology and risk factors of MASLD and provides an approach to screening, diagnosis, and treatment based on current best available evidence and expert opinion. What is known: • NAFLD/MASLD is a common disorder in children strongly related to obesity/overweight and insulin resistance. • This silent disorder is underdiagnosed due to lack of awareness and lack of simple diagnostic criteria. What is new: • New diagnostic criteria have transformed NAFLD/MASLD from a diagnosis of exclusion to a positive diagnosis with simple criteria. • Effective treatments are emerging for adults and will likely become available for children. • Identifying children with NAFLD/MASLD has become even more important due to this new treatment perspective.

The prospective study aimed to investigate the long-term associated risks of cirrhosis and hepatocellular carcinoma (HCC) across various subtypes of steatotic liver disease (SLD).

We enrolled 332,175 adults who participated in a health screening program between 1997 and 2013. Participants were categorized into various subtypes, including metabolic dysfunction-associated SLD (MASLD), MASLD with excessive alcohol consumption (MetALD), and alcohol-related liver disease (ALD), based on ultrasonography findings, alcohol consumption patterns, and cardiometabolic risk factors. We used computerized data linkage with nationwide registries from 1997 to 2019 to ascertain the incidence of cirrhosis and HCC.

After a median follow-up of 16 years, 4,458 cases of cirrhosis and 1,392 cases of HCC occurred in the entire cohort, resulting in an incidence rate of 86.1 and 26.8 per 100,000 person-years, respectively. The ALD group exhibited the highest incidence rate for cirrhosis and HCC, followed by MetALD, MASLD, and non-SLD groups. The multivariate adjusted hazard ratios for HCC were 1.92 (95% confidence interval [CI] 1.51-2.44), 2.91 (95% CI 2.11-4.03), and 2.59 (95% CI 1.93-3.48) for MASLD, MetALD, and ALD, respectively, when compared with non-SLD without cardiometabolic risk factors. The pattern of the associated risk of cirrhosis was similar to that of HCC (all P value <0.001). The associated risk of cirrhosis for ALD increased to 4.74 (95% CI 4.08-5.52) when using non-SLD without cardiometabolic risk factors as a reference.

This study highlights elevated risks of cirrhosis and HCC across various subtypes of SLD compared with non-SLD, emphasizing the importance of behavioral modifications for early prevention.

Obesity often coincides with non-alcoholic fatty liver disease (NAFLD), yet a significant portion of NAFLD patients exhibit normal body mass index (BMI) but have abdominal obesity. Recognizing this discrepancy, we aimed to delve deeper into this phenomenon through observational studies coupled with two-sample Mendelian randomization (MR) analysis, with waist-to-hip ratio (WHR) serving as the indicator for abdominal obesity. Our objective was to ascertain whether WHR correlates with an increased risk of NAFLD development.

This study utilized data from the National Health and Nutrition Examination Survey (NHANES) 2017-2018 to examine the association between WHR and NAFLD through weighted multivariate logistic regression models. On this basis, subgroup analyses were performed to further explore the correlation between WHR and NAFLD. Subsequently, a two-sample MR analysis was conducted using genome-wide association studies (GWAS) data to investigate the potential causal relationship between WHR and NAFLD. Sensitivity analyses were also employed to ensure the robustness of our findings.

A total of 3,732 eligible participants were included in the analysis. Weighted multivariable-adjusted logistic regression models revealed a positive association between WHR and the risk of NAFLD (Q2vsQ1: OR = 1.94 [95% CI: 1.55-2.44]; Q3vsQ1: OR = 2.08 [95% CI: 1.51-2.85]; Q4vsQ1: OR = 3.70 [95% CI: 2.13-6.43], p < 0.05). The results of the subgroup analysis suggested that there was an interaction in the correlation between WHR and NAFLD in normal weight, overweight, and obese populations (p < 0.05). The RCS curves indicated that there was a nonlinear relationship between WHR and NAFLD in populations with BMI in the normal versus obese categories. Furthermore, MR analysis provided additional support for the causal relationship between WHR and NAFLD. Using inverse variance weighting (IVW), the MR analysis yielded an OR of 2.062 (95% CI: 1.680-2.531, p<0.05). Consistent results were obtained with the other four MR methods, all supporting the same direction of causality. Sensitivity analyses were performed to assess the robustness of the findings (p > 0.5), further reinforcing the reliability of the observed associations.

WHR elevation heightens the susceptibility to NAFLD.

Recent efforts to reclassify non-alcoholic fatty liver disease (NAFLD) as metabolic dysfunction-associated fatty liver disease (MAFLD) and metabolic dysfunction-associated steatotic liver disease (MASLD) are intended to divert attention to the metabolic basis of the disease rather than to alcohol consumption. This reclassification recognizes the role of obesity, sedentary lifestyles and poor dietary habits in the development of the disease, leading to a better understanding of its etiology. Nevertheless, the transition has posed its own challenges, particularly with regard to communication between patient and healthcare professional. Many healthcare professionals report difficulty in explaining the nuanced concepts, especially the term "steatosis". In addition, the change in terminology has not yet removed the stigma, with ongoing debates about the appropriateness of the terms "fatty" and "steatotic". Surveys suggest that while "obesity" may be perceived as more stigmatizing, the medical term "steatotic liver disease" is not considered as stigmatizing, indicating a disconnect in perceptions between healthcare professionals and patients.

Recent data indicate the involvement of skeletal muscles in the regulation of metabolism and in the pathogenesis of chronic noncommunicable diseases. The goal of our study was to describe the serum concentrations of myokines in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and hypertension (HTN) and their correlation with laboratory parameters, blood pressure (BP), and MASLD severity.

A total of 67 patients with MASLD and HTN underwent anthropometric measurements, laboratory tests, and point shear-wave elastography. The serum concentrations of myokines were measured using enzyme-linked immunosorbent assay (ELISA).

Patients with detectable serum myonectin concentrations had significantly higher maximum systolic blood pressure (p = 0.022) and higher blood levels of uric acid (p = 0.029). Serum irisin concentration ≥ 6.1 μg/mL was associated with higher FLI values (p = 0.042) and liver stiffness (p = 0.034), as well as with slightly higher waist circumference (p = 0.082) and triglyceride level (p = 0.062). Patients with serum myostatin concentration ≥ 4.98 ng/mL were significantly older (p = 0.033) and had a lower blood albumin level (p = 0.043).

In conclusion, the myokine profile in patients with MASLD and HTN correlates both with the severity of MASLD and the parameters characteristic of metabolic health, suggesting the possible contribution of altered irisin, myonectin, and myostatin concentrations to the occurrence of cardiometabolic risks in patients with MASLD.

We aim to evaluate the prevalence of steatotic liver disease (SLD) in United States (US) adolescents and explore whether metabolic dysfunction-associated steatotic liver disease (MASLD) can identify individuals with clinically significant fibrosis (CSF) in this study. The prevalence of SLD and its categories, including MASLD, metabolic dysfunction and alcohol associated liver disease (MetALD), alcohol related liver disease (ALD) and other SLD were determined. Weighted multivariable logistic regression analysis was conducted to evaluate the association between MASLD and CSF in adolescents with SLD. Among the total 1,446 US adolescents, SLD was present in 291 (20.1%) of individuals, including 260 (17.9%) for MASLD, 9 (0.6%) for MetALD and 5 (0.3%) for ALD. Only 58 (4%) had CSF. Patients with SLD showed a higher prevalence of CSF (9.6% vs. 2.6%, p < 0.001). Among patients with SLD, 89.3% met the MASLD criteria. The risk of CSF in patients with MASLD was not significantly different (odds ratio [OR] = 1.07, 95% confidence interval [CI] = 0.30-3.83, p = 0.9180) compared with those without MASLD. MASLD was met by most of the US adolescents with SLD. Moreover, MASLD was not associated with higher prevalence of CSF among adolescents with SLD.

Background/Objectives: Prior research has identified a significant association between heart disease and metabolic-dysfunction-associated steatotic liver disease (MASLD); however, the underlying mechanisms are unclear. This study aimed to identify predictive biomarkers associated with grade I left ventricular diastolic dysfunction (LVDD) in patients with type 2 diabetes mellitus (T2DM). Methods: This single-center, cross-sectional study evaluated 73 T2DM patients for grade 1 LVDD and MASLD using 2D echocardiography, tissue analysis, spectral color Doppler, and Fibromax. Results: This study analyzed 50 patients (mean age 58.0 ± 11.3 years) with a median diabetes duration of 7 years, abdominal obesity (mean body mass index (BMI) 34.4 ± 5.9 kg/m2), and a mean HbA1c of 7.9 ± 1.5%. The prevalence of grade I LVDD, fibrosis, mild steatosis, moderate-to-severe liver steatosis, mild MASLD, and moderate MASLD was 54%, 44%, 14%, 80%, 43%, and 34%, respectively. Regression analysis revealed that grade 1 LVDD was positively associated with age, Fibrotest, α2-macroglobulin, epicardiac adipose tissue (EAT), and negatively associated with lateral s', E wave, E/e', E/A, medium E', and septal e' (p < 0.05 for all). α2-macroglobulin > 1.92 g/L (area under the receiver operating characteristic curve (AUROC) = 0.782, sensitivity 70.4%, specificity 81.2%) and fibrotest score > 0.11 (AUROC 0.766, sensitivity 92.6%, specificity 56.2%) were significant predictors of grade I LVDD. Conclusions: Although the underlying mechanisms remain unclear, innovative non-invasive biomarkers, such as α2-macroglobulin or fibrotest, could concurrently indicate liver stiffness and the likelihood of grade I LVDD, an early, asymptomatic HF stage in T2DM patients.

In 2020, a revised definition of fatty liver disease associated with metabolic dysfunction (MAFLD) was proposed to replace non-alcoholic fatty liver (NAFLD). Liver steatosis and at least one of the three metabolic risk factors, including type 2 diabetes, obesity, or signs of metabolic dysregulation, are used to diagnose MAFLD. MAFLD, similarly to NAFLD, is characterized by a spectrum of disease ranging from simple steatosis to advanced metabolic steatohepatitis with or without fibrosis, and may progress to cirrhosis and liver cancer, including increased risk of other critical extrahepatic diseases. Even though the pathophysiology of MAFLD and potential therapeutic targets have been explored in great detail, there is yet no Food and Drug Administration approved treatment. Recently, gut microbiome-derived products (e.g., endotoxins and metabolites) involved in intestinal barrier disruption, systemic inflammation, and modification of intrahepatic immunity have been associated with MAFLD development and progression. Therefore, different strategies could be adopted to modify the gut microbiome to improve outcomes in early and progressive MAFLD. Here, we provide an overview of mechanisms that may link the gut microbiome and immune response during the onset of liver steatosis and progression to steatohepatitis and fibrosis in patients with MAFLD. Finally, gut microbiota-based approaches are discussed as potential personalized treatments against MAFLD.

Liver fibrosis is a complication of metabolic dysfunction-associated steatotic liver disease (MASLD). Given the limitations and risks of liver biopsy, examining noninvasive scoring systems that are affordable for the population is necessary. Our aim was to evaluate and compare the diagnostic yield of the APRI, FIB-4, NAFLD score, and Hepamet fibrosis score instruments for detecting liver fibrosis in Mexican subjects with MASLD.

A retrospective study was conducted on a sample of subjects with MASLD. Liver fibrosis was calculated through transient liver elastography. Sociodemographic, epidemiologic, and biochemical variables were evaluated. Scores were calculated utilizing the fibrosis-4 (FIB-4) index, the aspartate aminotransaminase-to-platelet ratio index (APRI), the Hepamet fibrosis score (HFS), and the NAFLD score (NFS), and then compared. ROC curves were constructed, and the optimum cutoff points were determined utilizing the Youden index. Sensitivity, specificity, positive predictive value, negative predictive value, and likelihood ratio were calculated.

The study included 194 subjects (63% women), of whom 150 (77.3%) were classified with MASLD and 44 (22.7%) as controls with no liver disease. There was a 15.3% prevalence of advanced fibrosis. The cutoff points of 0.57 for APRI, 1.85 for FIB-4, 0.08 for HFS, and -0.058 for NFS showed diagnostic yields with areas under the ROC curves of 0.79, 0.80, 0.70, and 0.68, respectively.

The APRI, FIB-4, NFS, and HFS scores are useful for evaluating liver fibrosis in Mexican subjects with MASLD. Better diagnostic yield was found with the FIB-4 and APRI scores.

Steatotic liver disease (SLD) is a new overarching term proposed to replace nonalcoholic fatty liver disease and metabolic dysfunction-associated fatty liver disease. Subclassification includes metabolic dysfunction-associated SLD (MASLD), MASLD with increased alcohol intake (MetALD), and cryptogenic SLD. This study aimed to investigate whether SLD and its subclassification could stratify hepatocellular carcinoma (HCC) risk.

A cohort of 85,119 adults without viral hepatitis or heavy alcohol intake was analyzed for the risk of HCC according to SLD and its subclassification. The fibrosis-4 (FIB-4) index was used to estimate the degree of liver fibrosis.

During a median follow-up of 11.9 years, HCC was diagnosed in 123 individuals. The incidence rate of HCC per 1,000 person-years was higher in individuals with SLD than in those without SLD (0.197 vs. 0.071, p < 0.001), with an adjusted hazard ratio of 2.02 (95% confidence interval: 1.40-2.92). The HCC incidence rate per 1,000 person-years was 0, 0.180, and 0.648 for cryptogenic SLD, MASLD, and MetALD, respectively. When participants with SLD was further stratified by the FIB-4 index, the HCC incidence rate per 1,000 person-years was 0.074 for SLD with FIB-4 < 1.3 and 0.673 for SLD with FIB-4 ≥ 1.3. Of note, HCC risk was substantially high (HCC incidence rate: 1.847 per 1,000 person-years) for MetALD with FIB-4 ≥ 1.3.

HCC risk was different by SLD and its subclassification. The utilization of SLD and its subclassification can aid in stratifying HCC risk and facilitate the identification of individuals requiring interventions to mitigate the risk of HCC.

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease associated with metabolic dysfunction, ranging from hepatic steatosis with or without mild inflammation to nonalcoholic steatohepatitis, which can rapidly progress to liver fibrosis and even liver cancer. In 2023, after several rounds of Delphi surveys, a new consensus recommended renaming NAFLD as metabolic dysfunction-associated steatotic liver disease (MASLD). Ninety-nine percent of NAFLD patients meet the new MASLD criteria related to metabolic cardiovascular risk factors under the "multiple parallel hits" of lipotoxicity, insulin resistance (IR), a proinflammatory diet, and an intestinal microbiota disorder, and previous research on NAFLD remains valid. The NLRP3 inflammasome, a well-known member of the pattern recognition receptor (PRR) family, can be activated by danger signals transmitted by pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), as well as cytokines involved in immune and inflammatory responses. The activation of the NLRP3 inflammasome pathway by MASLD triggers the production of the inflammatory cytokines IL-1β and IL-18. In MASLD, while changes in the composition and metabolites of the intestinal microbiota occur, the disrupted intestinal microbiota can also generate the inflammatory cytokines IL-1β and IL-18 by damaging the intestinal barrier, negatively regulating the liver on the gut-liver axis, and further aggravating MASLD. Therefore, modulating the gut-microbiota-liver axis through the NLRP3 inflammasome may emerge as a novel therapeutic approach for MASLD patients. In this article, we review the evidence regarding the functions of the NLRP3 inflammasome and the intestinal microbiota in MASLD, as well as their interactions in this disease.

We conducted a comprehensive literature review to evaluate the efficacy of combining two-dimensional shear wave elastography (2D-SWE) and ultrasound-guided attenuation parameter (UGAP) in assessing the risk of progressive metabolic dysfunction-associated steatohepatitis (MASH). This narrative review explores the applications of liver ultrasound in diagnosing metabolic liver diseases, focusing on recent advancements in diagnostic techniques for steatotic liver disease (SLD). Liver ultrasound can detect a spectrum of SLD manifestations, from metabolic dysfunction-associated liver disease (MASLD) to fibrosis and cirrhosis. It is also possible to identify inflammation, hepatitis, hepatocellular carcinoma (HCC), and various other liver lesions. Innovative ultrasound applications, including elastography and UGAP, can significantly enhance the diagnostic capabilities of ultrasound in accurately interpreting liver diseases. Understanding the pathogenesis of liver diseases requires a thorough analysis of their etiology and progression in order to develop sound diagnostic and therapeutic approaches. Chronic liver diseases (CLD) vary in origin, with MASLD affecting approximately 20-25% of the general population. The insidious progression of CLD from inflammation to fibrosis and cirrhosis underscores the need for effective early detection methods. This review aims to highlight the evolving role of non-invasive ultrasound-based diagnostic tests in the early detection and staging of liver diseases. By synthesizing current evidence, we aim to provide an updated perspective on the utility of advanced ultrasound techniques in redefining the diagnostic landscape for metabolic liver diseases.

A recent name change of nonalcoholic fatty liver disease (NAFLD) or metabolic dysfunction-associated fatty liver disease (MAFLD) to metabolic dysfunction-associated steatotic liver disease was primarily driven by potential stigma associated with the terminology. This stigma can be different between patients and healthcare providers and differ according to geographic regions of the world. Our aim was to better understand stigma and disease burden among patients with NAFLD enrolled in the global survey from Saudi Arabia (SA).

Members of the Global NASH Council created a 68-item survey about patients' experience with NAFLD, covering history of stigmatization and discrimination due to the disease, various aspects of the disease burden [(Liver Disease Burden (LDB), 35 items, 7 domains], and perception of various diagnostic terms for NAFLD. Patients whose country of residence was SA were asked to complete the survey.

The survey was completed by 804 patients with NAFLD from SA. Of all enrolled patients, 17% ever disclosed having NAFLD/nonalcoholic steatohepatitis (NASH) to family/friends. The most commonly used term for the disease was "fatty liver" (96% used it at least sometimes, 79% frequently or always). There were 3.7% who reported experiencing stigma or discrimination (at least sometimes) due to obesity/overweight versus only 2.7% due to NAFLD. Female patients reported a history of stigmatization or discrimination more frequently than males: 5.9% versus 3.0% due to obesity ( P = 0.06) and 5.4% versus 1.8% due to NAFLD ( P = 0.01). There were 43% of patients who reported ever missing or avoiding a visit to a primary care provider due to NAFLD (48% male vs 28% female, P < 0.0001). The greatest social-emotional burden among patients with NAFLD (by LDB) was being or being identified as a person with liver disease (10% agree, 4% male vs 26% female) and feeling like they could not do anything about their liver disease (6.4% agree, 3% male vs 16% female). Regarding how patients perceived diagnostic terms, there were no substantial differences between "fatty liver disease", "NAFLD", "NASH", and "MAFLD".

Stigmatization in terms of disease burden, disease-related stigma, and perception of various diagnostic terms are rarely observed in patients with NAFLD in SA. In comparison to male patients, female patients with NAFLD reported more commonly a history of stigmatization and discrimination and a significantly greater disease burden. The findings will help inform policymakers to develop programs to increase awareness and provide education about stigma related to NAFLD.

Previous studies have shown that pyroptosis in hepatocyte is essential for the development of MAFLD. Growing evidence has shown that exosomal miRNAs-mediated communication between inflammatory cells and hepatocyte is an important link in MAFLD. In the present study, we aim to elucidate whether macrophage-derived exosomal miRNAs contribute to the hepatocyte pyroptosis in the pathophysiological process of MAFLD.

The effects of hepatocyte pyroptosis were investigated in an HFD-induced MAFLD mouse model and in the liver tissues from patients with MAFLD using immunohistochemistry, real-time PCR, Western blotting, and luciferase reporter assay, among other techniques. MiR-155 inhibitor tail injections and AAV-FoxO3a-GFP were also administered to respectively inhibit or overexpress its expression in an HFD-induced MAFLD mouse model.

Hepatocyte pyroptosis was heightened in the liver tissue of patients with MAFLD or HFD-induced MAFLD mouse. Importantly, treatment with a caspase-1 inhibitor or overexpression of FoxO3a reversed this trend. Our study also demonstrated that miR-155 expression and the number of infiltrated macrophages were increased, and knockdown of miR-155 attenuated hepotocyte pyroptosis and liver fibrosis in HFD-induced mouse. In addition, we demonstrated that macrophage-derived exosomal miR-155 was transferred to hepatocytes, leading to hepatocyte pyroptosis in MAFLD mouse. Furthermore, blockade of exosome secretion improved hepotocyte pyroptosis and liver fibrosis in HFD-induced mouse. On the contrary, macrophage-derived exosomal miR-155 worsened hepotocyte pyroptosis. Moreover, we found that miR-155 promoted hepatocyte pyroptosis in MAFLD by down-regulating FoxO3a.

Taken together, our results demonstrated that macrophage-derived exosomal miR-155 promotes hepatocyte pyroptosis and liver fibrosis in MAFLD.