Although liver biopsy is considered the most reliable diagnostic tool for metabolic dysfunction-associated steatohepatitis (MASH), it is invasive and can be costly. Clinicians are increasingly relying on routine biomarkers and other noninvasive tests (NITs) for diagnosis. We examined real-world diagnostic pathways for patients newly diagnosed with MASH with a primary focus on NITs.

This retrospective, observational study analyzed healthcare claims data (Merative MarketScan Commercial and Medicare Databases) from patients in the United States newly diagnosed with MASH from October 1, 2016, to March 31, 2023. Patients ≥18 years old with ≥12 months of continuous enrollment with medical and pharmacy benefits prior to diagnosis were included. Diagnostic pathways leading up to MASH diagnosis, including NITs (blood-based and imaging-based tests) and liver biopsies were assessed. Prevalence of comorbid conditions, MASH-associated medication use, and the diagnosing physician specialty were also examined.

A total of 18,396 patients were included in the analysis. Routine laboratory tests (alanine aminotransferase [ALT], albumin, aspartate aminotransferase [AST], cholesterol, complete blood count, and hemoglobin A1c) were performed among ≥70% of patients prior to MASH diagnosis, including 89% of patients with a liver enzyme test (ALT and/or AST). More than 75% of patients had necessary laboratory tests to calculate AST to platelet ratio index (APRI) and fibrosis-4 index (FIB-4) scores. The most common imaging performed was ultrasound (62%); liver biopsy was only performed in 10% of patients. There was a high prevalence of cardio metabolic risk factors such as hyperlipidemia (66%), hypertension (62%), obesity (58%), type 2 diabetes (40%), and cardiovascular disease (21%). Nearly half of the patients (49%) were diagnosed by a primary care physician.

This study highlights real-world diagnostic pathways among patients newly diagnosed with MASH, supporting previous findings that liver biopsies are infrequently used in favor of noninvasive methods.

Non-alcoholic fatty liver disease (NAFLD) is a complex metabolic disorder involving intertwined signaling pathways, posing challenges for targeted therapeutic interventions. Cornus Fructus (CF), a traditional medicinal herb, holds potential for NAFLD treatment, with cornuside (COR) identified as its primary active component.

This study employed a cross-disciplinary approach, integrating bioinformatics, computational chemistry, and machine learning to uncover COR's therapeutic mechanisms with precision and depth.

Using bioinformatics-driven analysis, 27 core targets were identified, revealing that COR modulated critical metabolic and inflammatory pathways. COR mitigated insulin resistance by regulating the AKT/GSK3β axis, enhanced cholesterol metabolism through LXR signaling, promoted fatty acid oxidation via PPARα activation, and suppressed inflammation by inhibiting NF-κB signaling. These results highlighted COR's ability to orchestrate multi-pathway regulation essential for restoring metabolic homeostasis in NAFLD. Molecular docking and molecular dynamics (MD) simulations provided atomistic insights, demonstrating COR's stable and high-affinity interactions with key targets. Additionally, machine learning algorithms enhanced target identification and pathway prediction, improving the precision and efficiency of the discovery process.

This study offered multi-scale mechanistic insights into COR's therapeutic effects on NAFLD, bridging experimental pharmacology and computational methods. The integration of bioinformatics, molecular simulation, and machine learning established a comprehensive framework for drug discovery, positioning COR as a promising candidate for NAFLD therapy and guiding future development of precision interventions.

Cardiovascular disease and metabolic dysfunction-associated steatotic liver disease are common conditions associated with high mortality and morbidity, yet opportunities for integrated prevention are underinvestigated. We explored the association between impairment in the liver (defined by increased iron-corrected T1 (cT1) time) and/or heart (reduced left ventricular ejection fraction ≤ 50) and risk of experiencing cardiovascular- or liver-related events or all-cause mortality among 28,841 UK Biobank participants who underwent magnetic resonance imaging. Using Cox proportional hazard models, adjusted for age, sex, body mass index, type 2 diabetes and dyslipidaemia, we observed that cardiac impairment was associated with increased incidence of cardiovascular events (hazard ratio (HR) 2.3 (1.9-2.7)) and hospitalization (HR 2.1 (1.8-2.4)). Liver impairment was associated with incident cardiovascular hospitalization (cT1 ≥ 800 ms, HR 1.3 (1.1-1.5)), liver events (cT1 ≥ 875 ms, HR 9.2 (3.2-26) and hospitalization (cT1 ≥ 875 ms, HR 5.5 (3.2-9.3). Associations between cT1 and liver events were maintained in participants with metabolic dysfunction-associated steatotic liver disease (N = 6,223). Reduced left ventricular ejection fraction (≤50) combined with elevated cT1 (≥800 ms) were associated with earlier cardiovascular events (time to event 0.8 versus 2.4 years; P < 0.05). Cardiac and liver impairment are independently, or in combination, associated with cardiovascular or liver events, suggesting a dual role for magnetic resonance imaging in integrated prevention pathways.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic and progressive liver disease with an increasing global burden that starts with an early stage of simple steatosis (MASL) which frequently progresses to liver cirrhosis and hepatocellular carcinoma (HCC). Despite its widespread occurrence, the MASL or steatotic stage, characterized by excessive fat accumulation in the liver and considered reversible and benign, has not been extensively studied. To study MASL effectively, it is imperative to have a clinically relevant model system that focuses solely on steatosis, in a progressive and time-dependent manner, recapitulating molecular changes associated with human disease. We established a chronic cellular model of MASL using a primary immortalized human hepatocyte cell line treated with a low dose mixture of fatty acids. This model mimics the pattern of chronic disease progression, shows minimal lipotoxicity, exhibits progressive lipid accumulation (from early to moderate steatosis), and demonstrates macrosteatosis, a hallmark of MASL. To determine whether this model recapitulates both morphological and molecular aspects of steatosis, we measured the expression of key genes and pathways found to be dysregulated in a recently available early MASL patient dataset as well as a non-human primate model of MASL. In support of the relevance of our model, we observed increased fatty acid uptake, lipogenesis, mitochondrial activity, metabolic rewiring, and autophagic alterations that significantly overlap with the pathological features of human and non-human primate MASL. In conclusion, we generate a relevant cellular model of steatosis that can serve as a robust platform for screening of existing chemical libraries to identify potent inhibitors of MASL as well as discovering novel therapeutic targets by mechanistically studying altered molecular signatures associating early stages of MASLD.

Noninvasive tests (NITs) are used to risk-stratify metabolic dysfunction-associated steatotic liver disease. The aim was to survey global patterns of real-world use of NITs.

A 38-item survey was designed by the Global NASH Council. Providers were asked about risks for advanced fibrosis, which NITs (cutoff values) they use to risk-stratify liver disease, monitor progression, and which professional guidelines they follow.

A total of 321 participants from 43 countries completed the survey (54% hepatologists, 28% gastroenterologists, and 18% other). Of the respondents, 85% would risk-stratify patients with type 2 diabetes, obesity (82%), or abnormal liver enzymes (73%). Among NITs to rule out significant or advanced fibrosis, transient elastography (TE) and fibrosis-4 (FIB-4) were most used, followed by NAFLD Fibrosis Score, Enhanced Liver Fibrosis, and magnetic resonance elastography. The cutoffs for ruling out significant fibrosis varied considerably between practices and from guidelines, with only 50% using TE <8 kPa, 65% using FIB-4 <1.30 for age <65, and 41% using FIB-4 <2.00 for age ≥65. Similar variability was found for ruling in advanced fibrosis, where thresholds of FIB-4 ≥2.67 and TE ≥10 kPa were used by 20% and 17%, respectively. To establish advanced fibrosis, 48% would use 2 NITs while 23% would consider 1 NIT, and 17% would confirm with liver biopsy. TE was used by >75% to monitor, and 66% would monitor (intermediate or high risk) annually. Finally, 65% follow professional guideline recommendations regarding NITs.

In clinical practice, there is variability in NIT use and their thresholds. Additionally, there is suboptimal adherence to professional societies' guidelines.

Background: Non-alcoholic steatohepatitis (NASH) is characterized by increased production of proinflammatory cytokines, fibrosis, and hepatocyte apoptosis. This study aimed to assess the efficacy of N-acetyl cysteine (NAC), rosuvastatin (RSV), and vitamin E (VE) in patients with NASH. Methods: A double-blinded, parallel, randomized, controlled study was conducted and registered on clinicaltrials.gov (Identifier: NCT06105060), involving 135 NASH participants, who were divided into three groups: the control group (group 1), consisting of patients receiving standard therapy VE at a dosage of 400 IU twice daily. In the treated group (group 2), patients were administered NAC at a dosage of 1200 mg twice daily, while treatment (group 3) received RSV at a dosage of 20 mg once daily. FibroScan® examination of liver tissue and fibrosis scores, along with tests for liver aminotransferases, lipid profile, glycemic parameters, and renal and hepatic functions, were assessed before and after six months of treatment. Results: The analyzed groups demonstrated a significant reduction in steatosis and lipid peroxidation (p < 0.05). The NAC group demonstrated greater anti-inflammatory and anti-apoptotic effects compared to the RSV group, although this difference was not significant in the control group. NAC is conceded as the only significant antifibrotic agent in liver stiffness measurement (LSM), biological marker findings, and non-invasive liver fibrosis scores (p < 0.05), in addition to its improvement of several metabolic parameters and health-related quality of life. Conclusions: Patients receiving NAC demonstrated safety and efficacy in enhancing steatosis, fibrosis, and metabolic parameters, representing a novel strategy in the management of NASH.

Metabolic associated fatty liver disease (MAFLD) represents a significant public health concern. Previous studies have shown that ACT001 has therapeutic effects on MAFLD. This study investigated the potential mechanisms by which ACT001 may treat MAFLD through an integrated approach of transcriptomics and metabolomics. MAFLD model induced by high-fat diet was established, and ACT001 was given by gavage. Histological analysis was performed, and liver enzyme and lipid levels were measured. Transcriptomic analysis was performed to identify differentially expressed genes, while metabolomic analysis was used to detect differential metabolites. Pathways enriched by genes and metabolites affected by ACT001 were also identified. The differentially expressed genes were confirmed through RT-qPCR. ACT001 reduced the levels of liver enzymes and lipids, and alleviated pathological damage such as hepatic steatosis. The integration of transcriptomic and metabolomic analyses indicated that ACT001 may alleviate high-fat diet-induced MAFLD by regulating the linoleic acid and glutathione metabolic pathways. The validation of five differentially expressed genes using RT-qPCR yielded results that were consistent with the transcriptomics data. ACT001 may exert a therapeutic effect in MAFLD mice by modulating glutathione metabolism and linoleic acid metabolism. It has the potential to be a promising treatment for MAFLD.

Nonalcoholic fatty liver disease (NAFLD) is increasingly recognized as a contributor to chronic kidney disease (CKD), yet its impact remains underappreciated in clinical practice. Recent studies reveal a strong association between NAFLD and CKD progression, with evidence linking hepatic dysfunction to renal impairment through metabolic and inflammatory pathways. NAFLD not only increases the risk of CKD but also accelerates its progression, leading to worse cardiovascular outcomes and higher mortality, particularly in patients with advanced fibrosis. Despite this growing evidence, NAFLD often goes undiagnosed in CKD patients and routine hepatic evaluation is rarely integrated into nephrology care. Emerging diagnostic tools, including noninvasive biomarkers and imaging techniques, offer potential for earlier detection, yet their clinical implementation remains inconsistent. Although lifestyle modifications remain the foundation of treatment, pharmacotherapeutic strategies, including SGLT2 inhibitors and GLP-1 receptor agonists, have demonstrated potential in mitigating both hepatic and renal impairment. Recognizing the interplay between NAFLD and CKD is essential for improving patient outcomes. A multidisciplinary approach, integrating hepatology and nephrology expertise, is crucial to refining screening strategies, optimizing treatment, and reducing the long-term burden of these coexisting conditions.

Using common clinical parameters, we aimed to noninvasively identify and predict metabolic dysfunction-associated steatohepatitis (MASH)/MASH with clinically significant fibrosis.

Patients aged ≥18 with electronic health record (EHR) documented liver function tests and liver biopsies between 2016 and 2021 were retrospectively identified from the Geisinger Health System Research Liver Registry. MASH cases were confirmed using the nonalcoholic fatty liver disease (NAFLD) activity score. Training and validation datasets were used to create an algorithm/predictive model assessing EHR-derived predictors of MASH/MASH with clinically significant fibrosis (fibrosis stage F2-F4). Predictive accuracy was evaluated using the area under the curve.

The analysis included 2698 patients. We created a composite likelihood score using variables significant for MASH and/or MASH with clinically significant fibrosis: liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST]), prior year AST, metabolic disease, pulse (heart rate), and body mass index. The score had higher sensitivity and specificity for predicting MASH than Fibrosis-4 (FIB-4) Index, AST to platelet ratio index (APRI), and NAFLD fibrosis score (NFS); sensitivity and specificity were comparable to FIB-4 and APRI for predicting MASH with clinically significant fibrosis but superior to NFS.

The composite likelihood score could potentially be a tool for early MASH screening.

Non-alcoholic fatty liver disease (NAFLD) is a leading cause of cirrhosis and a major risk factor for hepatocellular carcinoma and liver-related death. Diabetes medications have been studied as potential treatments for NAFLD. Glucagon-like peptide-1 agonists (GLP-1RAs) have been rarely reported in the treatment of NAFLD alone as an anti-diabetic drug, and its specific mechanism of action is unknown. We investigated whether the therapeutic effect of liraglutide (LRG, a representative drug of GLP-1RAs) on hepatic steatosis is related to regulating lipid metabolism and enhancing autophagy in the hepatocytes.

We examined the effect of LRG on fat accumulation in fatty hepatocytes, and discussed its effects on enzymes related to lipid metabolism and autophagy. Meanwhile, knockdown of SIRT1 in free fatty acids(FFA)-treated cells was used to detected the influence of LRG on lipid metabolism and autophagy by regulating of AMPK/SIRT1 signaling.

Our findings showed that free fatty acids (FFA) induced hepatocyte steatosis, which was significantly reversed by LRG. Meanwhile, LRG significantly regulated the expression of hepatocyte lipogenesis and cytosolic lipolysis-related proteins (FAS, ACC1, ATGL, HSL, LAL). Furthermore, LRG enhanced FFA-induced suppression of autophagy and SIRT1 expression, reducing intracellular lipid accumulation. It is evident that LRG regulates lipid metabolism and induces autophagy in an (AMPK)-dependent manner. Moreover, SIRT1 knockdown inhibited the autophagy-inducing and lipid-lowering effects of LRG.

GLP-1RAs may lower hepatic steatosis by regulating lipid metabolism and enhancing autophagy in an AMPK/SIRT1-dependent manner, providing a new target for the treatment of NAFLD.

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.

This study used the Global Burden of Disease data (2010-2021) to analyze the rates and trends of point prevalence, annual incidence, and years lived with disability (YLDs) for metabolic dysfunction-associated steatotic liver disease (MASLD) in 204 countries.

Total numbers and age-standardized rates per 100,000 population for MASLD prevalence, annual incidence, and YLDs were compared across regions and countries by age, sex, and sociodemographic index (SDI). Smoothing spline models were used to evaluate the relationship between the burden of MASLD and SDI. Estimates were reported with uncertainty intervals (UI).

Globally, in 2021, the age-standardized rates per 100,000 population of point prevalence of MASLD were 15,018.1 cases (95% UI 13,756.5-16,361.4), annual incidence rates were 608.5 cases (598.8-617.7), and YLDs were 0.5 (0.3-0.8) years. MASLD point prevalence was higher in men than women (15,731.4 vs. 14,310.6 cases per 100,000 population). Prevalence peaked at ages 45-49 for men and 50-54 for women. Kuwait (32,312.2 cases per 100,000 people; 95% UI: 29,947.1-34,839.0), Egypt (31,668.8 cases per 100,000 people; 95% UI: 29,272.5-34,224.7), and Qatar (31,327.5 cases per 100,000 people; 95% UI: 29,078.5-33,790.9) had the highest prevalence rates in 2021. The largest increases in age-standardized point prevalence estimates from 2010 to 2021 were in China (16.9%, 95% UI 14.7%-18.9%), Sudan (13.3%, 95% UI 9.8%-16.7%) and India (13.2%, 95% UI 12.0%-14.4%). MASLD incidence varied with SDI, peaking at moderate SDI levels.

MASLD is a global health concern, with the highest prevalence reported in Kuwait, Egypt, and Qatar. Raising awareness about risk factors and prevention is essential in every country, especially in China, Sudan and India, where disease incidence and prevalence are rapidly increasing.

This research provides a comprehensive analysis of the global burden of MASLD, highlighting its rising prevalence and incidence, particularly in countries with varying sociodemographic indices. The findings are significant for both clinicians and policymakers, as they offer critical insights into the regional disparities in MASLD burden, which can inform targeted prevention and intervention strategies. However, the study's reliance on modeling and available data suggests cautious interpretation, and further research is needed to validate these findings in clinical and real-world settings.

Chronic liver disease is a world-wide epidemic. Any etiology that causes inflammation in the liver will lead to chronic liver disease. Presently, the most common inciting factor worldwide is steatotic liver disease. Recent advances in ultrasound imaging provide a multiparametric ultrasound methodology of diagnosing, staging, and monitoring treatment of chronic liver disease. Elastography has become a standard of care technique for the evaluation of liver fibrosis. Quantitative ultrasound allows for determination of the degree of fatty infiltration of the liver. Portal hypertension is the most important factor in determination of liver decompensation. B-mode findings combined with Doppler, and elastography techniques provide qualitative and quantitative methods of determining clinically significant portal hypertension. A newer method using contrast enhanced ultrasound may allow for a non-invasive quantitative estimation of the portal pressures. This paper reviews the use of multiparametric ultrasound in the evaluation of chronic liver disease including conventional B-mode ultrasound, Doppler, elastography and quantitative ultrasound for estimation of liver fat. The recent guidelines are presented and advised protocols reviewed.

Posttranslational modifications (PTM) of albumin occur in liver diseases; however, little is known about the source and function of sulfonated albumin, a significant modification of albumin occurring in nonalcoholic fatty liver disease (NAFLD). We aimed to investigate the mechanism underlying sulfonated albumin production and its role in the progression of NAFLD-related liver fibrosis.

Serum samples from healthy controls and patients with NAFLD were used to measure the proportion of sulfonated albumin. Mice models with NAFLD fed with high-fat diet (HFD) and methionine choline-deficient diet (MCD) were constructed. RNA sequencing, KEGG analysis, and GSEA were used to explore the mechanism of sulfonated albumin production and its mechanism of activating hepatic stellate cells (HSCs) and promoting the progression of liver fibrosis in NAFLD.

Sulfonated albumin levels increased significantly in both human and mouse NAFLD serum samples. In vivo studies in mice have shown that the intraperitoneal injection of sulfonated albumin promotes inflammation, hepatic steatosis, and liver fibrosis in NAFLD. In addition, autophagy has been verified as a key mechanism in the regulation of sulfonated albumin production. We also demonstrated that reactive oxygen species (ROS) production depends on the accumulation of damaged mitochondria and affects the production of sulfonated albumin under the regulation of autophagy. Hepatocyte-derived sulfonated albumin activates HSCs through the GAL3 receptor, thereby activating the endoplasmic reticulum (ER) stress pathway and promoting profibrotic activation of HSCs.

Our study demonstrated that sulfonated albumin activated HSCs through GAL3, thereby accelerating NAFLD-related liver fibrosis. Serum sulfonated albumin may be a potential diagnostic marker for liver fibrosis and an important target for the treatment of NAFLD-related liver fibrosis.

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.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its more severe subtype, metabolic dysfunction-associated steatohepatitis (MASH), are highly prevalent and strongly associated with obesity and type 2 diabetes (T2D). This study sought to identify challenges to the diagnosis, treatment and management of people living with MASLD and MASH and understand the key barriers to adopting relevant clinical guidelines.

A real-world, cross-sectional study (BARRIERS-MASLD) consisting of a quantitative survey and qualitative interviews of physicians in France, Germany, Italy, Spain and the United Kingdom was conducted from March to September 2023. Descriptive statistics were used for data analysis.

A total of 626 physicians completed the survey; n = 10 from each country participated in the qualitative interviews. Physicians considered the presence of MASH to be highly impactful on how they treated people living with obesity (66%) and T2D (69%). Over one-third (35%) of the respondents could not identify any MASH-specific clinical guidelines issued by medical societies or associations top-of-mind, but overall awareness rose when prompted about country-specific guidelines. Physicians said they would need evidence of success (48%) and clinical guidelines that address common MASLD comorbidities (38%) to increase their adoption.

This study found that lack of awareness around MASLD and MASH clinical guidelines and clearly established care pathways, particularly for addressing common comorbidities, was a key factor preventing physicians from optimising care for people living with MASH in Europe. This research highlights opportunities to improve education and training about clinical guidelines and care coordination.

As the rates of obesity and type 2 diabetes (T2D) continue to increase globally, so does the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD). Currently, 38% of all adults and 7-14% of children and adolescents have MASLD. By 2040, the MASLD prevalence rate for adults is projected to increase to more than 55%. Although MASLD does not always develop into progressive liver disease, it has become the top indication for liver transplant in the United States for women and those with hepatocellular carcinoma (HCC). Nonetheless, the most common cause of mortality among patients with MASLD remains cardiovascular disease. In addition to liver outcomes (cirrhosis and HCC), MASLD is associated with an increased risk of developing de novo T2D, chronic kidney disease, sarcopenia, and extrahepatic cancers. Furthermore, MASLD is associated with decreased health-related quality of life, decreased work productivity, fatigue, increased healthcare resource utilization, and a substantial economic burden. Similar to other metabolic diseases, lifestyle interventions such as a heathy diet and increased physical activity remain the cornerstone of managing these patients. Although several obesity and T2D drugs are available to treat co-morbid disease, resmetirom is the only MASH-targeted medication for patients with stage 2-3 fibrosis that has approved by the Food and Drug Administration for use in the United States. This review discusses MASLD epidemiology and its related risk factors and outcomes and demonstrates that without further global initiatives, MASLD incidence could continue to increase.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a significant global health issue, affecting over 30% of the population worldwide due to the rising prevalence of metabolic risk factors such as obesity and type 2 diabetes mellitus. This spectrum of liver disease ranges from isolated steatosis to more severe forms such as steatohepatitis, fibrosis, and cirrhosis. Recent studies highlight the role of gut microbiota in MASLD pathogenesis, showing that dysbiosis significantly impacts metabolic health and the progression of liver disease. This review critically evaluates current microbiome-centered therapies in MASLD management, including prebiotics, probiotics, synbiotics, fecal microbiota transplantation, and emerging therapies such as engineered bacteria and bacteriophage therapy. We explore the scientific rationale, clinical evidence, and potential mechanisms by which these interventions influence MASLD. The gut-liver axis is crucial in MASLD, with notable changes in microbiome composition linked to disease progression. For instance, specific microbial profiles and reduced alpha diversity are associated with MASLD severity. Therapeutic strategies targeting the microbiome could modulate disease progression by improving gut permeability, reducing endotoxin-producing bacteria, and altering bile acid metabolism. Although promising, these therapies require further research to fully understand their mechanisms and optimize their efficacy. This review integrates findings from clinical trials and experimental studies, providing a comprehensive overview of microbiome-centered therapies' potential in managing MASLD. Future research should focus on personalized strategies, utilizing microbiome features, blood metabolites, and customized dietary interventions to enhance the effectiveness of these therapies.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common condition leading to chronic liver disease which generates substantial healthcare costs. Our aim was to model the impact of a hypothetical pharmacologic therapy which halts MASLD fibrosis progression on disease and economic burden.

The US MASLD disease burden model is a Markov model which forecasts disease progression and the impact of diagnosis and treatment. Diagnostic costs for all patients and direct costs for patients with MASLD-related liver disease were also incorporated. MASLD disease burden and economic impacts were modeled for five scenarios: a no treatment case and four interventions incorporating the impact of gradually increasing awareness, screening, and diagnosis, and treatment with anti-steatotic therapy and a future, hypothetical therapy that halts fibrosis progression.

Treatment with therapy which only reverses steatosis had minimal (<1 to 2%) effect on cumulative chronic liver disease cases and healthcare costs averted. The scenarios in which a hypothetical therapy halts fibrosis progression resulted in reductions in cases of decompensated cirrhosis (11-39%), hepatocellular carcinoma (10-34%), and liver-related deaths (8-31%), a 9-31% reduction in cumulative DALYs, and $40.5 to $99.1B incremental healthcare costs averted.

Increasing diagnosis and treatment for the MASLD population with moderate-to-advanced fibrosis will prevent advanced liver disease and death and will result in reducing the associated direct healthcare costs. Increasing awareness, screening and diagnosis along with introducing pharmacologic therapies that halt fibrosis progression are necessary to realize health and economic benefits for the MASLD population.

Metabolic dysfunction-associated steatotic liver disease (MASLD), the most rapidly increasing and prevalent cause of chronic liver disease, is associated with substantial healthcare costs. As disease burden and costs mount, pharmacologic therapy which halts MASLD fibrosis progression is coming to fruition. Modeling the impact on disease progression of a hypothetical pharmacologic therapy which halts MASLD fibrosis progression through multiple scenarios provides insights into the key drivers of the disease and costs associated with it. This should help to facilitate best policies and practices to mitigate the burden of MASLD.

Although numerous noninvasive steatosis indices have been developed to assess hepatic steatosis, whether they can be applied to young adults in the evaluation of metabolic dysfunction-associated steatotic liver disease (MASLD) remains uncertain.

Data from patients under 35 years of age who visited the Liver Health Clinic at the Armed Forces Goyang Hospital between July 2022 and January 2024 were retrospectively collected. Steatosis was diagnosed on the basis of a controlled attenuation parameter score ≥250 dB/m. MASLD was defined as the presence of steatosis in patients with at least one cardiometabolic risk factor.

Among the 1,382 study participants, 901 were diagnosed with MASLD. All eight indices for diagnosing steatosis differed significantly between the MASLD and non-MASLD groups (p<0.001). Regarding the predictive performance, the hepatic steatosis index (HSI), fatty liver index (FLI), Framingham steatosis index, Dallas steatosis index, Zhejiang University index, lipid accumulation product, visceral adiposity index, and triglyceride glucose-body mass index exhibited an area under the curve of 0.898, 0.907, 0.899, 0.893, 0.915, 0.869, 0.791, and 0.898, respectively. The cutoff values for the FLI and HSI were re-examined, indicating a need for alternative cutoff values for the HSI, with a rule-in value of 42 and a rule-out value of 36 in this population.

This study presents novel findings regarding the predictive performance of established steatosis markers in young adults. Alternative cutoff values for the HSI in this population have been proposed and warrant further validation.

Machine learning (ML) is a type of artificial intelligence that assists computers in the acquisition of knowledge through data analysis, thus creating machines that can complete tasks otherwise requiring human intelligence. Among its various applications, it has proven groundbreaking in healthcare as well, both in clinical practice and research. In this editorial, we succinctly introduce ML applications and present a study, featured in the latest issue of the World Journal of Clinical Cases. The authors of this study conducted an analysis using both multiple linear regression (MLR) and ML methods to investigate the significant factors that may impact the estimated glomerular filtration rate in healthy women with and without non-alcoholic fatty liver disease (NAFLD). Their results implicated age as the most important determining factor in both groups, followed by lactic dehydrogenase, uric acid, forced expiratory volume in one second, and albumin. In addition, for the NAFLD- group, the 5th and 6th most important impact factors were thyroid-stimulating hormone and systolic blood pressure, as compared to plasma calcium and body fat for the NAFLD+ group. However, the study's distinctive contribution lies in its adoption of ML methodologies, showcasing their superiority over traditional statistical approaches (herein MLR), thereby highlighting the potential of ML to represent an invaluable advanced adjunct tool in clinical practice and research.

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a spectrum of liver lesions, ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), that may further progress to cirrhosis. MASLD is estimated to affect more than one third of the general population and it represents a risk factor for end-stage liver failure and liver cancer, substantially contributing to liver-related morbidity and mortality. Although the pathogenesis of MASLD is incompletely understood, it is known to consist of a multifactorial process influenced by extrinsic and intrinsic factors such as metabolic, environmental and demographic features, gut microbiota and genetics. Dysregulation of both extracellular and intracellular lipid composition is known to promote the generation of toxic lipid species, thereby triggering lipotoxicity and cellular stress. These events ultimately lead to the activation of distinct cell death pathways, resulting in inflammation, fibrogenesis and, eventually, carcinogenesis. In this manuscript, we provide a comprehensive review of the role of lipotoxicity during MASLD pathogenesis, discussing the most relevant lipid species and related molecular mechanisms, summarizing the cell type-specific effects and highlighting the most promising putative therapeutic strategies for modulating lipotoxicity and lipid metabolism in MASLD.

Liver disease causes over two million deaths annually worldwide, comprising approximately 4% of all global fatalities. We aimed to analyze liver disease-related mortality trends from 1990 to 2021 using the World Health Organization (WHO) Mortality Database and forecast global liver disease-related mortality rates up to 2050.

This study examined age-standardized liver disease-related death rates from 1990 to 2021, employing data from the WHO Mortality Database across 112 countries across five continents. The rates over time were calculated using a locally weighted scatter plot smoother curve, with weights assigned based on the population of each country. Furthermore, this study projected liver disease-related mortality rates up to 2050 using a Bayesian age-period-cohort (BAPC) model. Additionally, a decomposition analysis was conducted to discern influencing factors such as population growth, aging, and epidemiological changes.

The estimated global age-standardized liver disease-related mortality rates surged significantly from 1990 to 2021 across 112 countries, rising from 103.4 deaths per 1,000,000 people (95% confidence interval [CI], 88.16, 118.74) in 1990 to 173.0 deaths per 1,000,000 people (95% CI, 155.15, 190.95) in 2021. This upward trend was particularly pronounced in low- and middle-income countries, in Africa, and in populations aged 65 years and older. Moreover, age-standardized liver disease-related mortality rates were correlated with a lower Human Development Index (P < 0.001) and sociodemographic index (P = 0.001). According to the BAPC model, the projected trend indicated a sustained and substantial decline in liver disease-related mortality rates, with an estimated decrease from 185.08 deaths per 1,000,000 people (95% CI, 179.79, 190.63) in 2021 to 156.29 (112.32, 214.77) in 2050. From 1990 to 2021, age-standardized liver disease-related deaths surged primarily due to epidemiological changes, whereas from 1990 to 2050, the impact of population aging and growth became the primary contributing factors to the overall increase.

Global age-standardized liver disease-related mortality has increased significantly and continues to emerge as a crucial global public health issue. Further investigation into liver disease-related mortality rates in Africa is needed, and updating policies is necessary to effectively manage the global burden of liver disease.

This study aims to examine the impact of sociodemographic and clinical factors on hepatocellular carcinoma (HCC) mortality in New South Wales (NSW), Australia.

We conducted a 15-year retrospective study (2001-2015) using data linkage of health records and cancer registry databases, to identify all HCC cases and analyse HCC-related and all-cause mortality rates. Location-based socioeconomic status (SES) was determined using the Socioeconomic Indexes for Areas (SEIFA). Multivariable Cox regression analysis was used to determine the effect of key variables on mortality.

5564 cases of HCC were diagnosed during the study period. A study cohort of 5454 cases was analysed after excluding cases with key missing data. More than half of the chronic liver disease cases were due to non-viral causes. During the study period, 4033 deaths occurred, of which 2862 were HCC-related. The median survival time for HCC-related deaths was 547 days, and the 5-year survival rate was 31.3 %. Higher HCC-related mortality rates were observed in SEIFA quintiles 2, 3 and 4, when compared to 5 (where SEIFA 1 is most disadvantaged, and SEIFA 5 is most advantaged). Furthermore, significantly increased HCC-related mortality was observed for those aged ≥65, male gender, Australian-born, hospitalisation due to complications of alcohol use, having metastatic HCC at diagnosis, and not receiving surgery for HCC.

There is higher prevalence of non-viral-related HCC than viral-related HCC in NSW, Australia, where HCC-related mortality risk is greatest among those Australian-born and lower to higher SES, when compared to highest SES. Identifying factors contributing to these emerging disparities is crucial for developing effective prevention programs and allocating research and health resources.

Steatotic liver disease is the overarching term for conditions characterised by abnormal lipid accumulation in the liver (liver or hepatic steatosis). Steatotic liver disease encompasses what was previously termed non-alcoholic fatty liver disease (NAFLD), which is now called metabolic dysfunction-associated steatotic liver disease (MASLD). Additionally, steatotic liver disease includes alcohol-related liver disease (ALD) and MetALD, the new classification for the overlap between MASLD and ALD, and rare causes of liver steatosis. Cirrhosis is globally the 11th leading cause of death, and steatotic liver disease has become the leading cause of cirrhosis in the EU and USA. Steatotic liver disease affects around 30% of the global population and is mainly driven by obesity, type 2 diabetes, and alcohol intake, but only a minor proportion with steatotic liver disease progress to cirrhosis. The presence and progression of liver fibrosis led by hepatic inflammation is the main predictor of liver-related death across the entire spectrum of steatotic liver diseases. A combination of recent advancements of widely available biomarkers for early detection of liver fibrosis together with considerable advancements in therapeutic interventions offer the possibility to reduce morbidity and mortality in patients with steatotic liver disease. This Seminar covers the recent reclassification of steatotic liver disease and how it reflects clinical practice and prognosis. For early detection of liver fibrosis, we propose a collaborative diagnostic framework between primary care and liver specialists. Lastly, we discuss current best practices for managing steatotic liver disease, we explore therapeutic targets across the spectrum of steatotic liver diseases, and we review the pipeline of drugs in development for MASLD.

The association between socioeconomic factors and disease severity is not well studied in people living with metabolic dysfunction-associated steatotic liver disease (MASLD). We thus examined if socioeconomic factors influence the presence of, or risk for future, major adverse liver outcomes (MALOs) in people living with MASLD.

We conducted a register-based cohort study that included all individuals with a MASLD diagnosis between 1987 and 2020 in Sweden. Logistic and Cox regression were used to examine the association between socioeconomic factors (country of birth, educational level, and marital status) and the presence of MALOs before or upon MASLD diagnosis or during follow-up, respectively.

In total, 14 026 people living with MASLD were identified, among whom the median age was 55 years, 50% were male and 775 (5.5%) had MALOs before or upon diagnosis. The adjusted odds ratio (aOR) for pre-existing MALOs was higher in divorced (aOR = 1.29, 95% confidence interval [CI] = 1.06-1.57) compared to married individuals. The aOR for pre-existing MALOs was lower among those with >12 years of education (aOR = .76, 95% CI = .62-.93) compared to individuals with an education level of 10-12 years. During a 5.2-year median follow-up, several socioeconomic factors were associated with increased rates of developing MALOs in a crude model; however, none were independently associated with incident MALOs after adjustment for confounders.

Socioeconomic factors were associated with somewhat higher odds for prevalent, but not incident, MALOs in people living with MASLD, after adjustments. This suggests primarily that risk factors for fibrosis progression are differently distributed across socioeconomic subgroups.

Lipid metabolism disorder is the primary feature of numerous refractory chronic diseases. Fatty acid oxidation, an essential aerobic biological process, is closely related to the progression of NAFLD. The forkhead transcription factor FOXO1 has been reported to play an important role in lipid metabolism. However, the molecular mechanism through which FOXO1 regulates fatty acid oxidation remains unclear.

Transcriptomic analysis was performed to examine the cellular expression profile to determine the functional role of FOXO1 in HepG2 cells with palmitic acid (PA)-induced lipid accumulation. FOXO1-binding motifs at the promoter region of aldehyde dehydrogenase 1 family member L2 (ALDH1L2) were predicted via bioinformatic analysis and confirmed via luciferase reporter assay. Overexpression of ALDH1L2 was induced to recover the impaired fatty acid oxidation in FOXO1-knockout cells.

Knockout of FOXO1 aggravated lipid deposition in hepatic cells. Transcriptomic profiling revealed that knockout of FOXO1 increased the expression of genes associated with fatty acid synthesis but decreased the expression of carnitine palmitoyltransferase1a (CPT1α) and adipose triglyceride lipase (ATGL), which contribute to fatty acid oxidation. Mechanistically, FOXO1 was identified as a transcription factor of ALDH1L2. Knockout of FOXO1 significantly decreased the protein expression of ALDH1L2 and CPT1α in vitro and in vivo. Furthermore, overexpression of ALDH1L2 restored fatty acid oxidation in FOXO1-knockout cells.

The findings of this study indicate that FOXO1 modulates fatty acid oxidation by targeting ALDH1L2.

Since 1980, the cumulative effort of scientists and health-care stakeholders has advanced the prerequisites to address metabolic dysfunction-associated steatotic liver disease (MASLD), a prevalent chronic non-communicable liver disease. This effort has led to, among others, the approval of the first drug specific for metabolic dysfunction-associated steatohepatitis (MASH; formerly known as nonalcoholic steatohepatitis). Despite substantial progress, MASLD is still a leading cause of advanced chronic liver disease, including primary liver cancer. This Perspective contextualizes the nomenclature change from nonalcoholic fatty liver disease to MASLD and proposes important considerations to accelerate further progress in the field, optimize patient-centric multidisciplinary care pathways, advance pharmacological, behavioural and diagnostic research, and address health disparities. Key regulatory and other steps necessary to optimize the approval and access to upcoming additional pharmacological therapeutic agents for MASH are also outlined. We conclude by calling for increased education and awareness, enhanced health system preparedness, and concerted action by policy-makers to further the public health and policy agenda to achieve at least parity with other non-communicable diseases and to aid in growing the community of practice to reduce the human and economic burden and end the public health threat of MASLD and MASH by 2030.

Relative fat mass (RFM) is a newly developed, sex-specific anthropometric formula designed to estimate total body fat percentage. However, research investigating the correlation between RFM and the risk of non-alcoholic fatty liver disease (NAFLD) remains limited. This study evaluates the association between RFM and the risk of NAFLD within the Japanese population.

This study including 14,250 Japanese adults who underwent physical examinations at Murakami Memorial Hospital between 2004 and 2015. We employed binary logistic regression to elucidate the direct relationship between RFM levels and the incidence of NAFLD. Additionally, a generalized additive model (GAM) coupled with smooth curve fitting techniques was utilized to map the non-linear association.

The cohort had an average age of 43.53 ± 8.89 years, with a male majority of 52.00%. NAFLD was identified in 17.59% of the participants. After adjusting for confounding factors, a significant positive correlation between RFM and NAFLD risk was observed (OR: 1.15, 95%CI: 1.10-1.21, P < 0.0001 for females; OR: 1.15, 95%CI: 1.10-1.19, P < 0.0001 for males). Additionally, a non-linear relationship between RFM and the incidence of NAFLD was detected in both genders. The RFM threshold was identified as 34.95 for women and 23.40 for men. RFM was positively associated with the risk of NAFLD when RFM was below the respective threshold (OR: 1.29, 95%CI: 1.19-1.40, P < 0.0001 for females; OR: 1.23, 95%CI: 1.17-1.29, P < 0.0001 for males), whereas no significant association was found when RFM was above the threshold (OR: 1.05, 95%CI: 0.98-1.12, P = 0.1829 for females; OR: 1.01, 95%CI: 0.95-1.08, P = 0.7392 for males).

Our findings suggest a positive, nonlinear relationship between RFM and the risk of NAFLD, with a saturation effect. These results imply that maintaining RFM at a lower level may be advantageous in mitigating the risk of NAFLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiometabolic conditions affect populations across economic strata. Nevertheless, there are limited epidemiological studies addressing these diseases in low (LICs) and lower-middle-income countries (lower MICs). Therefore, an analysis of the trend of MASLD and cardiometabolic conditions in these countries is necessary.

From 2000 to 2019, jointpoint regression analysis was employed to calculate the prevalence, mortality, and disability-adjusted life years (DALYs) for cardiometabolic conditions including MASLD, type 2 diabetes mellitus (T2DM), dyslipidemia (DLP), hypertension (HTN), obesity, peripheral artery disease (PAD), atrial fibrillation and flutter (AF/AFL), ischemic heart disease (IHD), stroke, and chronic kidney disease from HTN and T2DM, in LICs and lower MICs (according to the World Bank Classification 2019) using the Global Burden of Disease 2019 data.

Among the eleven cardiometabolic conditions, MASLD (533.65 million), T2DM (162.96 million), and IHD (76.81 million) had the highest prevalence in LICs and Lower MICs in 2019. MASLD represented the largest proportion of global prevalence in these countries (43 %). From 2000 to 2019, mortality in LICs and lower MICs increased in all cardiometabolic conditions, with obesity-related mortality having the highest increase (+134 %). During this timeframe, there were increased age-standardized death rates (ASDR) from obesity, PAD, and AF/AFL. From all conditions, the DALYs-to-prevalence ratio was higher in LICs and lower MICs than the global average.

The burden of MASLD and cardiometabolic conditions is increasing worldwide, with LICs and lower MICs experiencing higher (DALYs) disability per prevalence. As these conditions are preventable, counteracting these trends requires not only the modification of ongoing actions but also the strategizing of immediate interventions.

Glycotoxicity and lipotoxicity are key pathophysiological mechanisms underlying the development of metabolic associated fatty liver disease (MAFLD). The primary objective of this study is to investigate the association between the newly proposed Plasma-Glycosylated Hemoglobin A1c/High-Density Lipoprotein Cholesterol Ratio (HbA1c/HDL-C ratio) and the risk of MAFLD.

A study population of 14,251 individuals undergoing health examinations was included. The association between the HbA1c/HDL-C ratio and MAFLD was analyzed using multivariable logistic regression and restricted cubic spline (RCS) analysis. Exploratory analyses were conducted to assess variations in this association across subgroups stratified by gender, age, body mass index (BMI), exercise habits, drinking status, and smoking status. The discriminatory value of the HbA1c/HDL-C ratio and its components for screening MAFLD was evaluated using receiver operating characteristic (ROC) curves.

A total of 1,982 (13.91%) subjects were diagnosed with MAFLD. After adjusting for confounding factors, we found a significant positive association between the HbA1c/HDL-C ratio and MAFLD [odds ratio (OR) 1.34, 95% confidence interval (CI): 1.25, 1.44]. No significant differences in this association were observed across all subgroups (All P for interaction > 0.05). Furthermore, through RCS analysis, we observed a nonlinear positive correlation between the HbA1c/HDL-C ratio and MAFLD (P for non-linearity < 0.001), with a potential threshold effect point (approximately 3 for the HbA1c/HDL-C ratio). Beyond this threshold point, the slope of the MAFLD prevalence curve increased rapidly. Additionally, in further ROC analysis, we found that for the identification of MAFLD, the HbA1c/HDL-C ratio was significantly superior to HbA1c and HDL-C, with an area under the curve (AUC) and optimal threshold of 0.81 and 4.08, respectively.

Our findings suggest that the newly proposed HbA1c/HDL-C ratio serves as a simple and practical indicator for assessing MAFLD, exhibiting well-discriminatory performance in screening for MAFLD.