This study aimed to identify the worst "bad actors" in mixtures of pollutants contributing to liver damage and shorter telomeres in the U.S. population, using weighted quantile sum (WQS) modeling with stratification by race/ethnicity. We conducted a comprehensive cross-sectional analysis of mixtures of pollutants in National Health and Nutrition Examination Survey datasets: (1) 33,979 adults with blood levels of cadmium (Cd), lead (Pb), and mercury, including subsets with measurements of per-/polyfluoroalkyl substances (PFAS), and polychlorinated biphenyls (PCBs)/polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs); and (2) 7360 adults with measurements of telomeres, Cd, and Pb. Multivariable-adjusted WQS regression examined associations between WQS mixture indices and liver injury (alanine aminotransferase (ALT)-elevation), advanced liver-fibrosis (LF), and telomere length. WQSmetal indices were associated with advanced-LF in all racial/ethnic groups. The top contributor was Cd in the total population and in non-Hispanic Whites (NHW), while Pb was the top contributor in non-Hispanic Blacks (NHB). The WQSmetal-PCB-PCDD/F index was associated with ALT-elevation, with PCB126, Cd and Pb as main contributors; the odds ratio (OR) per decile was 1.50 (95 % CI, 1.26-1.78), while the OR per decile of the WQSmetal-PFAS index was 1.03 (95 % CI, 0.98-1.05), not significant. WQSmetal indices were associated with shorter telomeres. Cd was main contributor associated with advanced-LF in NHW, while Pb was the major bad actor in NHB, suggesting that NHB may be especially susceptible to Pb toxicity. Metals were associated with shorter telomeres. Metal and PCB/PCDD/F mixtures were associated with ALT-elevation. Heavy metals and organic chemicals may contribute to liver-related morbidity and healthcare disparities.

Liver fibrosis is an important predictor of mortality. Liver disease case definitions changed in 2023. These definitions include an easily over-looked group with no traditional etiology (NTE) of liver disease and no steatosis. We analyzed heavy metals and cardiometabolic risk factors (CMRFs) as fibrosis risk factors in the NTE group and in people with another newly-defined condition, metabolic dysfunction-associated steatotic liver disease (MASLD). Two National Health and Nutrition Examination Survey (NHANES) datasets were analyzed. In NHANES III (1988-1994), fibrosis and steatosis were defined by Fibrosis-4 scores and ultrasound, respectively, in 12,208 adults. In NHANES 2017-2020, fibrosis and steatosis were defined by transient elastography and the controlled attenuation parameter (CAP) in 5525 adults. Fibrosis risk factors varied over time and by race/ethnicity. In the earlier dataset, NTE-fibrosis had a positive, non-significant, association with high blood levels of lead (Pb). MASLD-fibrosis was associated with Pb (OR = 2.5, 95 % CI, 1.4-4.4) and not with CMRFs in non-Hispanic Blacks but was associated with CMRFs in non-Hispanic Whites. Heavy metal exposures fell between the two time periods. In the later dataset, NTE-fibrosis was associated with Pb (OR = 4.2, 95 % CI, 2.6-6.8) and cadmium (OR = 1.8, 95 % CI, 1.1-3.0) in the total population, but not with most CMRFs. MASLD-fibrosis was strongly-significantly associated with CMRFs in every racial/ethnic group except non-Hispanic Blacks in whom CMRFs were only weakly associated with MASLD-fibrosis. Heavy metal pollution, which disproportionately impacts minoritized populations, decreased over time, but remained strongly associated with liver fibrosis in people lacking traditional etiological factors for liver disease.

Non-Alcoholic Fatty Liver Disease (NAFLD) refers to a range of conditions marked by the buildup of triglycerides in liver cells, accompanied by inflammation, which contributes to liver damage, clinical symptoms, and histopathological alterations. Multiple molecular pathways contribute to NAFLD pathogenesis, including immune dysregulation, endoplasmic reticulum stress, and tissue injury. Both the innate and adaptive immune systems play crucial roles in disease progression, with intricate crosstalk between liver and immune cells driving NAFLD development. Among emerging therapeutic strategies, cell and gene-based therapies have shown promise. This study reviews the pathophysiological mechanisms of NAFLD and explores the therapeutic potential of cell-based interventions, highlighting their immunomodulatory effects, inhibition of hepatic stellate cells, promotion of hepatocyte regeneration, and potential for hepatocyte differentiation. Additionally, we examine gene delivery vectors designed to target NAFLD, focusing on their role in engineering hepatocytes through gene addition or editing to enhance therapeutic efficacy.

Non-alcoholic fatty liver disease (NAFLD) is a complex metabolic disorder, where the underlying molecular mechanisms are mostly not well-understood and therefore, warrants the need for therapeutic interventions targeting several metabolic pathways as a unified response. Of late, promising outcomes have been observed with mesenchymal stem cell-derived exosomes. However, reduced bioavailability due to systemic delivery and the need for repeated fresh isolation hinders their feasibility for clinical applications. In this regard, an 'off-the-shelf' 3D bioprinted hyaluronic acid-based hepatic patch to deliver encapsulated exosomes alone/or with hepatocytes (as dual-therapy) is developed as a holistic approach for ameliorating the disease condition and promoting tissue regeneration. The bioprinted hepatic patch demonstrated sustained and localized release of exosomes (∼82 % in 21 days), and healthy liver tissue-like mechanical properties while being biocompatible and biodegradable. Assessment in NAFLD rat models displayed alleviation of the altered biochemical parameters such as fat deposition, deranged liver functions, disrupted lipid, glucose, and insulin metabolism along with a reduction in localized inflammation, and associated liver fibrosis. The study suggests that a synergistic effect between the miRNA population of released exosomes, cell therapy, and the bioprinted matrix materials is crucial in targeting multiple complex metabolic pathways associated with the severity of the disease.

Heart failure with reduced ejection fraction (HFrEF) and metabolic dysfunction-associated steatotic liver disease (MASLD) are both associated with liver fibrosis. HFrEF patients may develop liver fibrosis due to hepatic congestion, MASLD, or a combination of both. The Fibrosis-4 (FIB-4) score calculated using age, aspartate aminotransferase, alanine aminotransferase, and platelet count, serves as a screening tool for advanced liver fibrosis. This study examines the association between the FIB-4 score and all-cause mortality, cardiovascular mortality, and major adverse liver outcomes (MALO) in patients with HFrEF.

This study included 4523 HFrEF patients from the Danish Heart Failure Registry. Based on FIB-4 score, 25.5 % were low-risk, 45.7 % were indeterminate-risk, and 28.8 % were high-risk for advanced liver fibrosis. After five years, the cumulative incidence of all-cause mortality was 43 % for the high-risk group, 36 % for the indeterminate-risk group, and 23 % for the low-risk group. The indeterminate-risk and high-risk group had an increased hazard ratio (HR) for all-cause mortality (HR 1.33, 95 % confidence interval [CI] 1.16-1.52; HR 1.51, 95 % CI 1.31-1.74) compared to the low-risk group. Similarly, HRs were elevated for cardiovascular mortality (HR 1.61, 95 % CI 1.27-2.05; HR 2.14, 95 % CI 1.67-2.74) and MALO (HR 1.77, 95 % CI 1.01-3.31; HR 2.54, 95 % CI 1.43-4.52).

A high FIB-4 score in patients with HFrEF is associated with increased mortality and MALO.

ATAD3A deficiency in hepatocytes has been shown to promote simple steatosis (SS). ATAD3 is upregulated in MCD diet-induced MASH. Since the MCD diet is commonly used to induce liver fibrosis, which is related to HSCs activation, we are prompted to investigate the functions of ATAD3 in these two cell types and their mediated transition from SS to MASH. To investigate the role of ATAD3A in HSCs, human LX-2 cells were treated with TGFβ. The results showed that ATAD3A expression was linked to the fibrotic markers ACTA2 and COL1A1. Knockdown of ATAD3A reversed TGFβ-induced HSC activation by downregulating both canonical (SMAD2/3) and non-canonical (ERK1/2 and p38 MAPK) TGFβ signaling pathways. To examine the effect of ATAD3 on the transition from SS to MASH, MASH was induced in mice using the GAN diet for 24 weeks. After 12 weeks, AAV8-conjugated Atad3 shRNA was administered to knock down Atad3 in the liver. This intervention suppressed steatosis and fibrosis while enhancing insulin sensitivity. Further analysis using conditioned medium (CM) from WT and ATAD3A KO Huh7 cells treated with LPS and PA revealed that IL-6 secretion from Huh7 hepatocytes activated HSCs. However, IL-6 secretion was diminished in ATAD3A KO CM. CM from ATAD3A KO cells also suppressed expression of fibrotic markers ACTA2, PP38, and P-SMAD3 compared to WT cells under MASH conditions. These data suggest that AAV8-mediated Atad3 silencing in hepatocytes prevents the transition from SS to MASH, at least in part, by downregulating IL-6 secretion to suppress HSC activation in MASH.

Compensated cirrhosis due to metabolic dysfunction-associated steatotic liver disease (CC-MASLD) increases morbidity and mortality risk but has no aetiology-specific treatment. We investigated the safety and efficacy signals of severe energy restriction.

In this randomised controlled trial, adults with CC-MASLD and obesity in a tertiary hepatology centre were randomised 2:1 to receive one-to-one remote dietetic support with a low-energy (880 kcal/day, 80 g protein/day) total diet replacement programme for 12 weeks and stepped food reintroduction for another 12 weeks or standard of care (SoC). Given the exploratory nature of the study, three pre-defined co-primary outcomes were used to assess safety and efficacy signals: severe increases in liver biochemistry, changes in iron-corrected T1, and changes in liver stiffness on magnetic resonance elastography. Changes in liver steatosis on magnetic resonance imaging, physical performance based on the physical performance test and liver frailty index, and changes in fat-free mass were secondary outcomes. Magnetic resonance outcomes were assessed blind.

Between February 2022 and September 2023, 17 participants (36% female, median [IQR] age 58 [7.5] years) were randomised to SoC (n = 6) or intervention (n = 11). The trial stopped earlier than planned due to slow recruitment rate. 91% and 94% of participants completed the intervention and attended the 24-week follow-up, respectively. Compared with the SoC, the between-group weight change in the intervention was -11.9 kg (95% CI: -17.2, -6.6, p < 0.001) at 24 weeks. Liver biochemistry markers (alanine transaminase, aspartate transaminase, and total bilirubin) were stable in everyone throughout the trial. Iron-corrected T1 and steatosis significantly reduced (-149.9 ms [95% CI -258.1, -41.7, p = 0.01] and -6% [95% CI -11.3, -0.6, p = 0.03], respectively). There were no between-group differences in changes in liver stiffness (0.2 kPa [95% CI -1.1, 1.6]), the physical performance test (1.5 points [95% CI -1.9 to 4.9], p = 0.70) or the liver frailty index (0 [95% CI -0.6 to 0.6], p = 0.97). Compared with SoC, absolute fat-free mass reduced (-3.2 kg [95% CI -6 to -0.3], p = 0.04) but relative fat-free mass as percentage of total body weight increased (5.4% [95% CI 0.5 to 10.3], p = 0.046). No participant met the pre-defined safety criteria for enhanced observation or intervention discontinuation. There was no between-group differences in changes in cardiovascular markers and no evidence of hepatic decompensation or serious adverse events.

Severe energy restriction appears a safe option to achieve significant weight loss and reduce liver fat without adverse effects in people with CC-MASLD. A larger study is needed to confirm these findings.

ISRCTN13053035, prospectively registered, overall study status: closed.

Liver fibrosis resulting from nonalcoholic fatty liver disease (NAFLD) and metabolic disorders is highly prevalent in patients with severe obesity and poses a significant health challenge. However, there is a lack of data on the effectiveness of noninvasive factors in predicting liver fibrosis. Therefore, this study aimed to assess the relationship between these factors and liver fibrosis through a machine learning approach.

This study involved 512 patients who underwent bariatric surgery at an outpatient clinic in Mashhad, Iran, between December 2015 and September 2021. Patients were divided into fibrosis and non-fibrosis groups and demographic, clinical, and laboratory variables were applied to develop four machine learning models: Naive Bayes (NB), logistic regression (LR), Neural Network (NN) and Support Vector Machine (SVM).

Among the 28 variables considered, six variables including (fasting blood sugar (FBS), skeletal muscle mass (SMM), hemoglobin, alanine transaminase (ALT), aspartate transaminase (AST) and triglycerides) showed high area under the curve (AUC) values for the diagnosis of liver fibrosis using 2D shear wave elastography (SWE) with LR (0.73, 95% CI: 0.65, 0.81) and SVM (0.72, 59% CI: 0.64, 0.80) models. Furthermore, the highest sensitivities were reported with SVM (0.83, 95% CI: 0.72, 0.91) and NB (0.66, 95% CI: 0.53, 0.77) models, respectively.

The predictive performance of six noninvasive factors of liver fibrosis was significantly superior to other factors, showing high application and accuracy in the diagnosis and prognosis of liver fibrosis.

The online version contains supplementary material available at 10.1007/s40200-025-01564-1.

Nonalcoholic fatty liver disease (NAFLD) is characterized by increased lipid accumulation and excessive deposition of extracellular matrix (ECM) that results in tissue stiffening. The potential interplay between matrix stiffness and hepatocyte lipid accumulation during NAFLD has not been established. Here, an in vitro NAFLD model is developed using chemically defined, engineered hydrogels and human induced pluripotent stem cell-derived hepatic organoids (HOs). Specifically, dynamic covalent chemistry crosslinking, along with transient small molecule competitors, are used to create dynamic stiffening hydrogels that enable the reproducible culture of HOs. Within matrices that mimic the stiffness of healthy to diseased tissue (≈1-6 kPa), lipid droplet accumulation in HOs is triggered by exposure to an NAFLD-associated free fatty acid. These NAFLD model suggests that higher stiffness microenvironments result in increased hepatic lipid droplet accumulation, increased expression of fibrosis markers, and increased metabolic dysregulation. By targeting the ROCK mechanosignaling pathway, the synergy between matrix stiffness and lipid droplet accumulation is disrupted. The in vitro model of NAFLD has the potential to understand the role of mechanosignaling in disease progression and identify new pathways for therapeutic intervention.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is primarily managed through diet and lifestyle modifications. However, these behavioural interventions alone may not achieve disease regression or remission, and maintaining long-term adherence is challenging. Incretin mimetics and other gastrointestinal hormones targeting the pleiotropic pathophysiological pathways underlying MASLD have now emerged as promising disease-modifying therapies.

This is a comprehensive review summarising the role of glucagon-like peptide-1 (GLP-1) receptor agonists and glucagon/glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor dual or triple agonists in the treatment of metabolic dysfunction-associated steatohepatitis (MASH).

Only clinical trials with endpoints assessed by liver histology were included for a robust evaluation of therapeutic efficacy.

Recent evidence from phase 2 clinical trials for MASH demonstrated that pharmacological agents based on GLP-1 receptor agonism are effective in improving disease activity. Additionally, tirzepatide and survodutide showed potential clinical benefits in reducing fibrosis. Other cardiometabolic benefits observed include weight loss and improvements in glycaemic control and lipid profile. Adherence to treatment may be limited by gastrointestinal side effects, though they were found to be generally mild to moderate in severity. An interim analysis of the semaglutide phase 3 trial confirmed its efficacy in improving steatohepatitis and demonstrated its potential to improve fibrosis.

GLP-1 receptor agonists, alone or in combination with GIP and/or glucagon receptor agonists, represent promising, effective pharmacotherapies for the treatment of MASLD/MASH. Larger and longer-duration clinical trials are needed to further evaluate the efficacy and safety of GIP receptor and glucagon receptor agonism.

The favor effect on liver disease by odium-glucose cotransporter inhibitor (SGLT2i) and GLP-1 receptor agonist (GLP1Ra) was reported; however, the effect of the combination treatment of these drugs was not well known.

We retrospectively analyzed data for 643 patients with type 2 diabetes receiving SGLT2i + GLP1Ra combination treatment for at least 1 year (331 and 312 patients in the GLP1Ra- and SGLT2i-preceding groups, respectively). Propensity score (PS) matching was used to compare the effects of the preceding drugs on liver function.

The mean AST and ALT values at baseline, at the initiation of combination treatment, and at final observation were 29.8 ± 20.0 and 37.7 ± 29.5, 28.7 ± 17.3 and 35.3 ± 6.0, 26.0 ± 14.6 and 30.1 ± 21.6 IU/L, respectively, indicative of significant improvements in liver function (P < 0.001). Conversely, significant progress in the fibrosis-4 (FIB-4) index category was observed even after the combination treatment (P = 0.03). Subgroup analysis revealed that a significant decrease in ALT was observed only in patients with a baseline ALT ≥30 IU/L after the combination treatment (P = 0.005). Improvement of the FIB-4 index category was observed in patients in the baseline FIB-4 index ≥2.6 group and in the 1.3 ≤FIB-4 index <2.6 group (46% and 19%, respectively). The matched model showed no significant differences in liver function after combination treatment between the SGLT2i- and GLP1Ra-preceding groups.

SGLT2i + GLP1Ra combination treatment significantly improved liver dysfunction and prevented the progression of FIB-4 index category among patients with an FIB-4 index ≥1.3.

In recent years, lactylation, a novel post-translational modification, has demonstrated a unique role in bridging cellular metabolism and epigenetic regulation. This modification exerts a dual-edged effect in both cancer and non-cancer diseases by dynamically integrating the supply of metabolic substrates and the activity of modifying enzymes: on one hand, it promotes tissue homeostasis and repair through the activation of repair genes; on the other, it exacerbates pathological progression by driving malignant phenotypes. In the field of oncology, lactylation regulates key processes such as metabolic reprogramming, immune evasion, and therapeutic resistance, thereby shaping the heterogeneity of the tumor microenvironment. In non-cancerous diseases, including neurodegeneration and cardiovascular disorders, its aberrant activation can lead to mitochondrial dysfunction, fibrosis, and chronic inflammation. Existing studies have revealed a dynamic regulatory network formed by the cooperation of modifying and demodifying enzymes, and have identified mechanisms such as subcellular localization and RNA metabolism intervention that influence disease progression. Nevertheless, several challenges remain in the field. This article comprehensively summarizes the disease-specific regulatory mechanisms of lactylation, with the aim of providing a theoretical foundation for its targeted therapeutic application.

Large language models like ChatGPT have demonstrated potential in medical image interpretation, but their efficacy in liver histopathological analysis remains largely unexplored. This study aims to assess ChatGPT-4-vision's diagnostic accuracy, compared to liver pathologists' performance, in evaluating liver fibrosis (stage) in metabolic dysfunction-associated steatohepatitis.

Digitized Sirius Red-stained images for 59 metabolic dysfunction-associated steatohepatitis tissue biopsy specimens were evaluated by ChatGPT-4 and 4 pathologists using the NASH-CRN staging system. Fields of view at increasing magnification levels, extracted by a senior pathologist or randomly selected, were shown to ChatGPT-4, asking for fibrosis staging. The diagnostic accuracy of ChatGPT-4 was compared with pathologists' evaluations and correlated to the collagen proportionate area for additional insights. All cases were further analyzed by an in-context learning approach, where the model learns from exemplary images provided during prompting.

ChatGPT-4's diagnostic accuracy was 81% when using images selected by a pathologist, while it decreased to 54% with randomly cropped fields of view. By employing an in-context learning approach, the accuracy increased to 88% and 77% for selected and random fields of view, respectively. This method enabled the model to fully and correctly identify the tissue structures characteristic of F4 stages, previously misclassified. The study also highlighted a moderate to strong correlation between ChatGPT-4's fibrosis staging and collagen proportionate area.

ChatGPT-4 showed remarkable results with a diagnostic accuracy overlapping those of expert liver pathologists. The in-context learning analysis, applied here for the first time to assess fibrosis deposition in metabolic dysfunction-associated steatohepatitis samples, was crucial in accurately identifying the key features of F4 cases, critical for early therapeutic decision-making. These findings suggest the potential for integrating large language models as supportive tools in diagnostic pathology.

Glucagon-like peptide 1 receptor agonist (GLP-1RA) therapies deliver histological benefit in people with metabolic dysfunction-associated steatotic liver disease (MASLD). Multiple mechanisms may be important including weight loss, improved glycaemic control and putative direct tissue-specific actions. Following cessation of GLP1-RA therapy, weight regain is common. To dissect the mechanisms underpinning their benefits, we conducted a prospective, randomised, experimental medicine study in people with MASLD, comparing GLP-1RA treatment (liraglutide) to matched lifestyle-induced weight loss and assessed the impact of treatment withdrawal.

Twenty-nine participants with MASLD, without type 2 diabetes underwent metabolic phenotyping including measurement de novo lipogenesis (DNL), liver magnetic resonance imaging, body composition, adipose tissue RNA sequencing, circulating proteome, and stool microbiome analysis. Participants were randomised to lifestyle (∼500 kcal energy deficit) or GLP1-RA treatment for 12 weeks, after which investigations were repeated, and treatment stopped; investigations were also repeated 12 weeks after treatment withdrawal.

Matched weight loss was achieved in both arms. Body composition changes, reductions in alanine aminotransferase, liver steatosis, and disease activity were similar following both treatments. GLP-1RA treatment, but not lifestyle, improved glucose handling, fasting lipids, and significantly deceased DNL. The subcutaneous adipose transcriptome, circulating proteome profile and stool microbiome were not different between groups after treatment. However, 12 weeks after GLP1-RA (but not lifestyle) withdrawal, circulating MMP-10, IL10RB, FGF-23, and Flt3L were elevated, alongside dysregulated adipose gene expression.

Although matched weight loss through lifestyle or GLP-1RA have comparable effects on hepatic steatosis, GLP-1RA treatment had additional metabolic benefits on glucose homeostasis, lipid profiles, and DNL. However, GLP-1RA withdrawal may adversely impact the circulating proteome, adipose tissue gene expression, and the stool microbiome, predisposing to weight regain.

Weight loss, through either lifestyle intervention or pharmacotherapy with GLP-1RA has an equally beneficial impact on the liver, and both strategies should be considered in the management of people with MASLD. GLP-1RA therapy may have additional benefits to improve glucose homeostasis even in the absence of pre-existing type 2 diabetes. Further research is needed to explore the differential impact of treatment withdrawal and the resultant metabolic consequences.

This study is registered at EudraCT (2016-002045-36).

The aim of this study is to analyze association between liver fibrosis with CVE, incident diabetes, and cirrhosis complications.

Historic cohort of biopsy-proven MASLD patients, divided into two groups: F0-F2 vs F3-F4 fibrosis. Baseline data included metabolic traits and liver function tests. Patients were contacted and scheduled for laboratory analysis and elastography. Endpoints were (a) CVE, defined as any of acute myocardial infarction, coronary stenting, ischemic cardiopathy, and stroke; (b) incident diabetes; (c) cirrhosis complications. Baseline data were collected at the time of liver biopsy, while follow-up data were recovered through personal interview or medical records. A stepwise logistic regression determined predictive variables for each endpoint.

Study population included 220 patients with median age 53 years, and 145 were women; baseline fibrosis was F0-F2 in 165 patients and F3-F4 in 55 patients; median follow-up was 9.9 years. A higher percentage of F3-F4 patients had CVE (29.4%) than F0-F2 ones (13.1%) (hazard ratio 2.42; 95% CI: 1.26-4.6; P  = 0.008). Incident diabetes occurred in 53.3% of F3-F4 and 20.2% of F0-F2 cohort (hazard ratio 3.04; 95% CI: 1.99-4.86; P  < 0.001); cirrhosis complications occurred in 9/55 F3-F4 patients and in 1/165 F0-F2 ones (hazard ratio 26.3; 95% CI: 3.3-208.3; P  = 0.002). Multivariate analysis confirmed liver fibrosis as an independent predictor of incident diabetes and cirrhosis complications. CVE were associated with baseline diabetes and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio.

In a cohort of 220 MASLD patients followed for 9.9 years, baseline F3-F4 was associated with incident diabetes and cirrhosis complications. AST/ALT ratio and diabetes were associated with CVE.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with poorer liver-related outcomes in type 2 diabetes (T2D) patients. We compared risk of liver-related outcomes and all-cause mortality between sodium-glucose cotransporter-2 inhibitor (SGLT-2i) users and nonusers in T2D patients.

We identified 282,161 T2D patients from the Taiwan National Health Insurance Research Database (2009-2020), excluding those with viral hepatitis or alcohol-related disorders. Propensity score matching created patient pairs on SGLT-2i and other antidiabetic drugs, and Cox proportional hazard models assessed outcomes.

Over a mean follow-up of 2.7 years, SGLT-2i use was associated with significantly lower risk of liver cirrhosis (adjusted hazard ratio [aHR] 0.78, 95 % CI: 0.70-0.87), decompensated cirrhosis (aHR 0.79, 95 % CI: 0.70-0.89), liver failure (aHR 0.78, 95 % CI: 0.68-0.89), and all-cause mortality (aHR 0.52, 95 % CI: 0.51-0.54). Compared to dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), pioglitazone, and sulfonylureas, SGLT-2i use was associated with lower risk of cirrhosis, liver failure, and all-cause mortality. SGLT-2i use was associated with lower liver-related mortality than DPP-4i or GLP-1 RA use.

This cohort study suggests that SGLT-2i may reduce the risk of liver cirrhosis, decompensated cirrhosis, liver failure, and liver-related and all-cause mortality in T2D patients.

There are limited data on the progression of liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) in people with type 2 diabetes mellitus (T2DM) versus those without T2DM in biopsy-proven metabolic dysfunction-associated steatotic liver disease. We examined LSM progression in participants with T2DM versus those without T2DM in a large, prospective, multicenter cohort study.

This study included 1231 adult participants (62% female) with biopsy-proven metabolic dysfunction-associated steatotic liver disease who had VCTEs at least 1 year apart. LSM progression and regression were defined by a ≥20% increase and an upward or downward change, respectively, in the LSM category in the Baveno VII categories for compensated advanced chronic liver disease, compared between participants with T2DM (n = 680) versus no T2DM (n = 551) at baseline. The mean (±SD) age and body mass index were 51.8 (±12.0) years and 34.0 (±6.5) kg/m 2 , respectively. The median (IQR) time between the first and last VCTE measurements was 4.1 (2.5-6.5) years. Participants with T2DM had higher LSM progression at 4 years (12% vs. 10%), 6 years (23% vs. 16%), and 8 years (50% vs. 39%), p = 0.04. Using a multivariable Cox proportional hazards model adjusted for multiple confounders, the presence of T2DM remained an independent predictor of LSM progression (adjusted HR: 1.35, 95% CI: 1.01-1.81, p = 0.04). T2DM was not associated with LSM regression ( p = 0.71). Mean HbA1c was significantly associated with LSM progression ( p = 0.003) and regression ( p = 0.02).

Using serial VCTE data from a multicenter study of participants with biopsy-proven metabolic dysfunction-associated steatotic liver disease, we demonstrate that T2DM and HbA1c are associated with LSM progression.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is emerging as the leading cause of chronic liver disease worldwide, reflecting the global epidemics of obesity, metabolic syndrome, and type 2 diabetes. Beyond its strong association with excess adiposity, MASLD encompasses a heterogeneous population that includes individuals with normal body weight ("lean MASLD") highlighting the complexity of its pathogenesis. This disease results from a complex interplay between genetic susceptibility, epigenetic modifications, and environmental factors, which converge to disrupt metabolic homeostasis. Adipose tissue dysfunction and insulin resistance trigger an overflow of lipids to the liver, leading to mitochondrial dysfunction, oxidative stress, and hepatocellular injury. These processes promote hepatic inflammation and fibrogenesis, driven by cross talk among hepatocytes, immune cells, and hepatic stellate cells, with key contributions from gut-liver axis perturbations. Recent advances have unraveled pivotal molecular pathways, such as transforming growth factor-β signaling, Notch-induced osteopontin, and sphingosine kinase 1-mediated responses, that orchestrate fibrogenic activation. Understanding these interconnected mechanisms is crucial for developing targeted therapies. This review integrates current knowledge on the pathophysiology of MASLD, emphasizing emerging concepts such as lean metabolic dysfunction-associated steatohepatitis (MASH), epigenetic alterations, hepatic extracellular vesicles, and the relevance of extrahepatic signals. It also discusses novel therapeutic strategies under investigation, aiming to provide a comprehensive and structured overview of the evolving MASLD landscape for both basic scientists and clinicians.

To investigate the relationship between serum uric acid (SUA) levels and metabolic dysfunction-associated steatotic liver disease (MASLD) in newly diagnosed type 2 diabetic patients.

We performed this retrospective research among 1087 inpatients with new-onset type 2 diabetes millitus (T2DM). Data were analyzed according to gender. Then, the populations were stratified according to their body mass index (BMI) levels in men and women, respectively. The physical and biochemical indicators were measured and recorded. The relationship between SUA and MASLD was estimated using logistic regression analysis, and the unadjusted and adjusted odds ratios (ORs) were calculated.

After adjusting for age, BMI, and other components of the metabolic syndrome, SUA was independently associated with MASLD only in men, but not in women. In addition, for men, the SUA levels were independently associated with MASLD in both non-overweight/obesity and overweight/obesity group. However, for women, the SUA levels were independently related to MASLD in non-overweight/obesity group. There was no association between SUA and MASLD in women with overweight/obesity.

In newly diagnosed type 2 diabetic patients, elevated SUA is an independent predictor for the risk of MASLD in males. In females, the relationship between SUA and MASLD may depend on BMI, with significance only in non-overweight/obese individuals.

Conventional histopathological evaluation of liver biopsy slides has been invaluable in assessing the causes of liver injury, the severity of the underlying disease processes, and the degree of resulting fibrosis. However, the use of conventional histologic assessments as endpoints in clinical trials is limited by the reliability of scoring systems, variability in interpretation of histologic features and translation of continuous variables into categorical scores. To increase the precision and reproducibility of liver biopsy assessment, several artificial intelligence/machine learning (AI/ML) approaches have been developed to analyse high resolution digital images of liver biopsy specimens. Multiple AI/ML platforms are in development with promising results in post-hoc analyses of clinical trial biopsies. One such technique employs images generated by Second Harmonic Generation/Two Photon Excitation (SHG/TPE) microscopy that uniquely uses unstained liver biopsies to provide high resolution images of collagen fibres to assess and quantify collagen morphometry, and avoid challenges related to staining variability. One SHG/TPE microscopy methodology coupled with AI/ML based analysis, qFibrosis™, has been used post-hoc as an exploratory endpoint in several clinical trials for metabolic dysfunction-associated steatohepatitis (MASH) demonstrating its ability to provide a consistent and more nuanced assessment of liver fibrosis that still correlates well with traditional staging. This review summarizes the development of qFibrosis and outlines the need for additional studies to validate it as a sensitive marker for changes in fibrosis in the context of treatment trials and correlate these changes with subsequent liver-related outcomes.

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

Objective Recent developments in ultrasound elastography (UE) and ultrasound attenuation imaging (UA) have enabled the detection of advanced liver fibrosis and steatosis in patients with steatotic liver disease (SLD), which is prevalent worldwide. In patients with SLD, the presence of advanced liver fibrosis determines the risk of hepatocarcinogenesis, and UE and UA are expected to play important roles in liver cancer surveillance. We conducted a questionnaire survey among medical facilities in Saga Prefecture regarding the actual status of awareness and implementation of UE and UA. Methods A 16-item questionnaire was sent to 275 facilities that employed members of the Liver Cancer Control Medical Association in Saga Prefecture. The response rate was 56% (153 facilities), and data from 142 facilities were analyzed after excluding 11 facilities. Results The most common facilities were outpatient clinics (60%) followed by hospitals with ≥100 beds (14%). In 48% of the facilities, an average of 10-49 abdominal ultrasound examinations were performed monthly. The rates of recognition that UE and UA are useful for fibrosis and steatosis were 65% (92/142) and 41% (58/142), respectively. The actual availability of UE and UA in facilities with ultrasound machines was 21% (30/142) and 12% (17/142), respectively; UE and UA were used in 90% (27/30) and 88% (15/17) of these facilities, respectively. Conclusion Even among medical facilities in Saga Prefecture that are active in liver cancer surveillance, awareness of UE and UA is not high. The availability of UE and UA may be inadequate, considering the high prevalence of SLD.

Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) prevent fibrosis progression in a preclinical model of steatotic liver disease. Our objective was to assess the impact of ACEi/ARB use on clinical outcomes in patients with metabolic dysfunction-associated steatotic liver diseases.

Using TriNetX, a nationwide database, we identified all patients with metabolic dysfunction-associated steatotic liver diseases from January 1, 2011, to December 31, 2019. Using a target trial emulation framework, ACEi/ARB users were matched with calcium channel blocker (CCB) users using propensity score matching (PSM). Patients were followed up to 10 years after the index date. Cox proportional hazards regression was used to determine the risk of mortality, major adverse liver outcomes, major adverse cardiac events, and incident cancers. Of the 35,988 eligible patients, 28,423 were ACEi/ARB users, and 7565 were CCB users. After PSM, 7238 pairs were well-balanced. ACEi/ARB use was associated with a significantly decreased mortality risk (HR: 0.59, 95% CI: 0.51-0.68). ACEi/ARB was associated with a significantly reduced risk of developing major adverse liver outcomes (HR: 0.70, 95% CI: 0.61-0.80), including ascites (HR: 0.78, 95% CI: 0.63-0.98) and HE (HR: 0.67, 95% CI: 0.57-0.78). ACEi/ARB use was also associated with a lower risk of major adverse cardiac events (HR: 0.82, 95% CI: 0.76-0.90) but not incident cancer (HR: 0.97, 95% CI: 0.86-1.10) compared with CCB.

ACEi/ARB use in patients with metabolic dysfunction-associated steatotic liver diseases was associated with a reduced risk of mortality, major adverse liver outcomes, and major adverse cardiac events compared with CCB use. A large prospective study is needed for external validation.

To elucidate the regional distribution of metabolic dysfunction-associated steatohepatitis (MASH) fibrosis within the liver and to identify potential therapeutic targets for MASH fibrosis.

Liver sections from healthy controls, patients with simple steatosis and MASH patients were analysed using spatial transcriptomics integrated with single-cell RNA-seq.

Spatial transcriptomics analysis of liver tissues revealed that the fibrotic region (Cluster 9) was primarily distributed in lobules, with some fibrosis also found in the surrounding area. Integration of the single-cell-sequencing data set (GSE189175) showed a greater proportion of inflammatory cells (Kupffer cells and T cells) and myofibroblasts in MASH. Six genes, showing high- or low-specific expression in Cluster 9, namely, ADAMTSL2, PTGDS, S100A6, PPP1R1A, ASS1 and G6PC, were identified in combination with pathology. The average expression levels of ADAMTSL2, PTGDS and S100A6 on the pathological HE staining map were positively correlated with the increase in the degree of fibrosis and aligned strongly with the distribution of fibrosis. ADAMTSL2+ myofibroblasts play a role in TNF signalling pathways and in the production of ECM structural components. Pseudotime analysis indicated that in the early stages of MASH, infiltration by T cells and Kupffer cells triggers a significant inflammatory response. Subsequently, this inflammation leads to the activation of hepatic stellate cells (HSCs), transforming them into myofibroblasts and promoting the development of liver fibrosis.

This study is the first to characterise lineage-specific changes in gene expression, subpopulation composition, and pseudotime analysis in MASH fibrosis and reveals potential therapeutic targets for this condition.

Metabolic-associated fatty liver disease (MAFLD) is a prevalent condition with significant health and economic burdens. Dietary interventions, such as intermittent fasting (IF) and low-calorie diets (LCD), have shown promise in managing MAFLD, but their comparative efficacy remains unclear.

This 10-month, parallel, single-blind randomized controlled trial compared the effects of a 16:8 IF diet with an LCD on 52 patients with MAFLD. Anthropometric, biochemical, liver enzyme, steatosis, fibrosis, inflammatory, and oxidative status parameters were assessed before and after the interventions.

Both diets led to improvements in anthropometric measures and liver enzyme levels, with no significant differences between groups. However, the LCD group showed superior outcomes in reducing liver steatosis (-52.40 vs -44.63 dB/m; P < 0.001) and fibrosis (-0.74 vs -0.004 Kpa; P = 0.01) compared to the IF group. LCD also led to a significant decrease in serum triglycerides (-24.08 vs 11.22 mg/dL; P = 0.02), while neither intervention significantly affected inflammatory markers or oxidative status.

While both IF and LCD can be effective in managing MAFLD, LCD may offer additional benefits in terms of liver fat reduction and improvement in certain lipid parameters. These findings highlight the complexity of dietary interventions in MAFLD and the need for personalized approaches.

Resmetirom, liver-directed thyroid-hormone receptor-β agonist, received approval for metabolic dysfunction-associated steatohepatitis (MASH) treatment. We assessed health-related quality of life (HRQL) in patients with MASH treated with resmetirom.

Patients with MASH/NASH without cirrhosis and with confirmed/suspected fibrosis were enrolled in a 54-month double-blind randomized placebo-controlled phase III clinical trial with serial biopsy assessments at baseline and week 52 (MAESTRO-NASH, NCT03900429). HRQL was assessed using Chronic Liver Disease Questionnaire-NASH (CLDQ-NAFLD) and Liver Disease Quality of Life (LDQOL). Baseline HRQL score changes by treatment group (resmetirom 80 mg, resmetirom 100 mg, or placebo) and histological response (improvement of fibrosis without worsening of NAFLD activity score or resolution of MASH/NASH without worsening of fibrosis) were compared after 52 weeks. Included were 966 intention-to-treat patients: 323 received resmetirom 100 mg, 322 resmetirom 80 mg, and 321 placebo. By weeks 24 and 52, patients receiving 80 or 100 mg resmetirom experienced HRQL improvement in CLDQ-NAFLD Worry domain (mean +0.21 to +0.24, p < 0.05). At week 52, subjects who met histologic endpoints after treatment with resmetirom (100 mg and 80 mg pooled) experienced HRQL improvement in CLDQ-NAFLD Worry +0.46 (41% met minimal clinically important difference [MCID]), LDQOL domains: Role Emotional +3.0 (28% met MCID), Health Distress +8.1 (38% MCID), Stigma +3.5 (39% MCID), and total LDQOL +2.2 (35% MCID) (all p < 0.05). Similar improvements were noted in histologic responders from 100 mg or 80 mg resmetirom groups when separated-no improvements in placebo or nonresponders. Baseline F3 histologic responders had similar/more pronounced HRQL improvements.

Patients with MASH/NASH with fibrosis improvement or the resolution of MASH with resmetirom experienced clinically meaningful and statistically significant HRQL improvements.

Several scientific associations recommend a sequential combination of non-invasive tests (NITs) to identify high-risk MASLD patients but their cost-effectiveness is unknown.

A cost-utility model was developed to assess the incremental cost-effectiveness ratio (ICER) of recommended screening strategies for patients with clinically suspected MASLD, specifically those with type 2 diabetes (T2D) and obesity with multiple cardiometabolic risk factors which will be initiated in primary care. Six screening strategies were assessed, using either vibration-controlled transient elastography (VCTE) or the enhanced liver fibrosis (ELF) test as a second-line test following an initial Fibrosis-4 (FIB-4) assessment as the first line NIT. The model included treatment effects of resmetirom for metabolic dysfunction-associated steatohepatitis (MASH) patients with F2 or F3 fibrosis.

All screening strategies for high-risk MASLD in US incurred additional costs compared to no screening, ranging from $13 587 to $14 730 per patient with T2D and $14 274 to $15 661 per patient with obesity. However, screening reduced long-term costs, ranging from $22 150 to $22 279 per patient with T2D and $13 704 to $13 705 per patient with obesity, compared to $24 221 and $14 956 for no screening, respectively. ICERs ranged from $26 913 to $27 884 per QALY for T2D patients and $23 265 to $24  992 per QALY for patients with obesity. While ICERs were influenced by VCTE availability, they remained cost-effective when using ELF as the second-line test. Our findings remain robust across a range of key parameters.

Screening for high-risk MASLD is cost-effective according to recent guidelines. Implementing these screening strategies in primary care should be considered.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing public health problem. The secondary stage in MASLD is steatohepatitis (MASH), the co-existence of steatosis and inflammation, a leading cause of progression to fibrosis and mortality. MASH resolution alone improves survival. Currently, MASH diagnosis is via liver biopsy. This study sought to evaluate the accuracy of imaging-based tests for MASH diagnosis, which offer a non-invasive method of diagnosis.

Eight academic literature databases were searched and references of previous systematic reviews and included papers were checked for additional papers. Liver biopsy was used for reference standard.

We report on 69 imaging-based studies. There were 31 studies on MRI, 27 on ultrasound, five on CT, 13 on transient elastography, eight on controlled attenuation parameter (CAP) and two on scintigraphy. The pathological definition of MASH was inconsistent, making it difficult to compare studies. 55/69 studies (79.71%) were deemed high-risk of bias as they had no preset thresholds and no validation. The two largest groups of imaging papers were on MRI and ultrasound. AUROCs were up to 0.93 for MRE, 0.90 for MRI, 1.0 for magnetic resonance spectroscopy (MRS) and 0.94 for ultrasound-based studies.

Our study found that the most promising imaging tools are MRI techniques or ultrasound-based scores and confirmed there is potential to utilise these for MASH diagnosis. However, many publications are single studies without independent prospective validation. Without this, there is no clear imaging tool or score currently available that is reliably tested to diagnose MASH.

MASLD is a leading reason for liver transplant waitlisting. The relationship between cardiorespiratory fitness (CRF) and liver fibrosis in patients with MASLD remains unclear. This study aims to provide further evidence supporting the relationship between liver fibrosis and CRF.

Participants with MASLD across various fibrosis stages, including those with cirrhosis awaiting liver transplantation from three U.S. transplant centers, underwent cardiopulmonary exercise testing (CPX). We compared participants based on fibrosis stage (F0-F1, F2-F3, and F4) and CPX parameters such as VO2peak, respiratory exchange ratio (RER), ventilatory efficiency (VE/VCO2), double product (DP) and chronotropic incompetence (CI). Multivariable models were then built to evaluate factors associated with these parameters.

Sixty-one participants underwent CPX testing across three centers. Participants with F4 had lower VO2peak (11.8 mL/kg/min) compared to F0-F1 (22.2 mL/kg/min) and F2-F3 (22.9 mL/kg/min), p < 0.001. Participants with F4 had higher RER (median 1.25) compared to F0-F1 (1.08) and F2-F3 (1.05), p = 0.001. Similarly, F4 participants exhibited higher VE/VCO2 (median 36.5) compared to F0-F1 (31) and F2-F3 (30), p < 0.001. Additionally, F4 participants had lower DP values (median 17,696) compared to F0-F1 (25,460) and F2-F3 (25,372), and higher prevalence of CI (90%) compared to F0-F1 (39%) and F2-F3 (25%), both p =  < 0.001. Multivariable modeling confirmed advanced fibrosis (F > 3) as an independent predictor of low CRF.

In MASLD patients, advanced liver fibrosis, particularly cirrhosis, is associated with reduced CRF and poorer hemodynamic performance during CPX. Prioritizing exercise training for those in earlier stages (F3) may prevent fitness decline, which could hinder physical training and liver transplantation candidacy.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent pediatric liver disease, yet accurate risk scores for referral of children/adolescents with suspected clinically significant liver fibrosis are currently lacking.

Clinical and biochemical variables were collected in a prospective cohort of 327 children and adolescents with severe obesity, in whom liver fibrosis was evaluated by transient elastography. Logistic regression was performed to establish continuous (pFIB-c) and simplified (pFIB-6) diagnostic scores that accurately exclude significant (≥F2) fibrosis. Performance for each was compared to established noninvve fibrosis scores. These scores were validated in elastography (n=504) and multiple biopsy-proven MASLD (n=261) cohorts. Patient sex, ethnicity, weight z-score, homeostatic model assessment of insulin resistance index, ALT, and presence of hypertension were included in the scores. The pFIB-c and pFIB-6 exhibited good discriminatory capacity (c-statistic of 0.839 and 0.826), outperforming existing indices. Negative predictive values were >90% for both scores in the derivation and elastography validation cohorts. Performance in the histological cohorts varied (AUROCs for the pFIB-c between 0.710 and 0.770), as the scores were less accurate when applied to populations in tertiary referral centers characterized by a high prevalence of significant fibrosis and high ALT levels.

Analyzing several cohorts totaling approximately 1100 children and adolescents, we developed novel risk scores incorporating readily available clinical variables. In accordance with the aim of excluding pediatric MASLD-associated fibrosis, the scores performed better in nonselected cohorts of children and adolescents living with obesity than in patients referred to tertiary liver units.

Transient elastography (TE) has become a prominent technique for the detection of fibrosis, owing to its non-invasive nature, rapid execution, safety, and ease of repetition. This study aims to conduct a bibliometric analysis of the historical development and trends in the application of TE for the assessment of liver fibrosis.

In the Web of Science (Core Collection database), we selected the Science Citation Index Expanded database to search for relevant literature from 1 January 1983 to 20 November 2023. We performed a search using the following topic words: transient elastography, liver fibrosis. After screening according to the title, abstract and keyword and removing the repetition, the literature included in the study was finally determined, and full records were downloaded. Bibliometric analysis was performed using VOSviewer and CiteSpace.

Through the bibliometric visualization analysis of 577 articles, it was found that since TE was first reported for the measurement of liver fibrosis in 2003, the number of publications in this field has generally shown an upward trend, and the distribution of publications has shown a bimodal distribution, with peaks in 2010 and 2019. France and China have shown a high contribution in this field with a high number of publications. In terms of contributions from individual research centers, Yonsei University stands out prominently. Throughout the history of research in this field, early studies focused on chronic viral hepatitis, by comparing TE and Fibrosis-4, aspartate aminotransferase to platelet ratio index, FibroTest, liver biopsy and other liver fibrosis detection indicators to verify its diagnostic efficacy. Subsequently, the focus of research gradually shifted to non-alcoholic fatty liver disease and other liver diseases, and the scope of research extended to the establishment of prediction models and efficacy evaluation through TE.

The application scope of TE is gradually expanding, and its safety, simplicity, rapidity, high accuracy, quantitative results, repeatability and good tolerance make it popular in clinical practice. Nowadays, the application of TE is not limited to the diagnosis of liver fibrosis, but has been extended to the establishment of prognostic models and efficacy evaluation of various liver diseases. To explore the deeper value of TE through new research methods such as machine learning models, radiate the advantages of TE to more liver diseases, and combine TE with a variety of non-invasive detection indicators to improve its application value, may be the future development and application prospect of TE in the field of liver fibrosis.

Metabolic dysfunction associated steatohepatitis (MASH), previously referred to as nonalcoholic steatohepatitis (NASH), has emerged as one of the leading indications for liver transplantation in the United States. The disease is associated with increased cardiovascular mortality in patients with early-stage liver fibrosis and a heightened risk of hepatic complications in those with advanced fibrosis. Despite its growing prevalence and significant healthcare burden, there were no approved drugs to treat this chronic disease. In March 2024, Resmetirom, a selective thyroid hormone receptor-beta agonist, became the first drug to receive FDA approval for the treatment of patients with MASH and fibrosis stages F2/F3. This accelerated approval was granted based on significantly higher rates of MASH resolution and fibrosis.

This review summarizes the current literature on the mechanism of action, preclinical data, pharmacokinetics, clinical efficacy, indications, and contraindications of resmetirom in the management of patients with MASH.

The approval of resmetirom for patients with MASH and moderate to advanced hepatic fibrosis is a major advance in the management of MASH. The recent positive results of the ESSENCE trial of semaglutide, if associated with conditional approval, may offer clinicians two options to treat MASH in patients with moderate to advanced fibrosis.

The effects of metabolic syndrome (MetS), its individual components, and baseline liver histology, on the rates of progression and regression of nonalcoholic fatty liver disease (NAFLD), were evaluated.

We conducted a post hoc analysis of a multicenter prospective cohort study using the noninterventional registry of the Nonalcoholic Steatohepatitis Clinical Research Network (2002-2022). We included patients aged 18 years or older with biopsy-proven NAFLD. Outcomes included progression/regression of histology defined by changes in NAFLD Activity Score, nonalcoholic steatohepatitis, or fibrosis. Crude incidence rates were compared among patients with MetS vs those without using Kaplan-Meier curves and log-rank test. Cox proportional hazard models were used to estimate effects of MetS and its components on the fibrosis progression/regression.

We included 452 patients; the mean age was 51 years, one-third was male, and 85% was White. The median follow-up was 4.3 (range: 1-15.6) years. At baseline, patients with MetS, large waist circumference, and impaired glucose tolerance/diabetes had worse ballooning and fibrosis scores and a higher prevalence of definite nonalcoholic steatohepatitis than those without. MetS was not associated with fibrosis progression or regression. Impaired glucose tolerance/diabetes was associated with a higher risk of fibrosis progression (adjusted hazard ratio = 1.61; 95% confidence interval: 1.11-2.34) whereas hypertension was associated with a lower risk (adjusted hazard ratio = 0.64; 95% confidence interval: 0.43-0.96).

In the cohort of patients with NAFLD, MetS was associated with greater histological severity at baseline but was not a risk factor of disease progression or regression. Impaired glucose/diabetes was associated with a higher rate and hypertension with a lower rate of fibrosis progression.

To evaluate the concordance between vibration-controlled transient elastography (VCTE) and magnetic resonance elastography (MRE) for staging liver fibrosis and assessing hypothetical eligibility for resmetirom treatment in a cohort of patients with metabolic dysfunction-associated steatotic liver disease (MASLD). A secondary objective was to assess the performance of VCTE for liver fat quantification.

This retrospective study included 103 patients (61 males; mean age 54.7 years) with suspected MASLD who underwent VCTE and MRI/MRE. The following parameters were extracted: liver stiffness (LS) from both techniques, controlled attenuation parameter (CAP) from VCTE, and MRI-proton density fat fraction (PDFF). Agreement and fibrosis stage distributions were assessed using Cohen's Kappa and McNemar's tests. ROC analysis assessed the performance of CAP against MRI-PDFF (considered the reference for steatosis).

A significant difference was observed in assigned fibrosis stage distributions between VCTE and MRE across all combinations (F0-F1 vs F2-F4, F0-F2 vs F3-F4, F0-F3 vs F4, all p < 0.001) with fair to moderate agreement between modalities (Cohen's Kappa values 0.305-0.554). VCTE assigned a higher fibrosis stage in 42 patients (40.7%). Thirty-three vs eighteen patients were classified as F2-F3 (qualified for resmetirom treatment) with VCTE vs MRE (Cohen's Kappa 0.215), which was associated with estimated cost savings of $707,701/year with MRE. VCTE-CAP achieved AUCs of 0.547, 0.754, and 0.813 for diagnosing mild, moderate, and severe steatosis, respectively.

VCTE and MRE have fair to moderate agreement for fibrosis staging, with VCTE tending to assign a higher fibrosis stage compared to MRE. VCTE-CAP reliably detects only severe steatosis.

Question What is the agreement between VCTE and MRE in staging fibrosis in MASLD and identifying patients with F2-F3 disease? Findings Limited concordance was found between VCTE and MRE for staging liver fibrosis and identifying F2-F3 disease; VCTE tended to assign higher fibrosis stages compared to MRE. Clinical relevance MRE could represent the modality of choice for selecting patients with metabolic dysfunction-associated steatohepatitis for resmetirom therapy as it potentially offers high cost-savings compared to VCTE.

To estimate the risks of coronary artery and cerebrovascular diseases in metabolic dysfunction-associated fatty liver disease (MAFLD) using different fatty liver index (FLI) cut-off values in a Japanese population.

We analyzed insurance claims and health checkup data from public medical insurance enrollees aged ≥40 years in seven Japanese municipalities who had undergone a health checkup between April 2015 and March 2022. The MAFLD cases were identified as hepatic steatosis (defined as FLI ≥60 or ≥37) with overweight/obesity, diabetes, or lean/normal weight with metabolic dysregulation. Cox proportional hazards models estimated adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for MAFLD (reference: non-MAFLD) regarding incident coronary artery and cerebrovascular diseases. Covariates included age, sex, smoking habit, low-density lipoprotein cholesterol level, and statin use.

The study was undertaken using 163 834 individuals. The HRs of MAFLD for coronary artery disease were 1.44 (95% CI, 1.24-1.67) for FLI ≥ 60 and 1.49 (95% CI, 1.32-1.68) for FLI ≥ 37. The HRs of MAFLD for cerebrovascular disease were 1.58 (95% CI, 1.22-2.05) for FLI ≥ 60 and 1.41 (95% CI, 1.15-1.74) for FLI ≥ 37. In women, neither FLI cut-off was associated with coronary artery disease, and only FLI ≥ 60 was associated with cerebrovascular disease.

The MAFLD cases identified using the two FLI cut-off values were at higher risk for coronary artery and cerebrovascular diseases. Asian-specific FLI cut-offs may better identify hepatic steatosis in Japan than Western-specific cut-offs, but there is a need to consider sex differences when determining at-risk subgroups for targeted health interventions.