Nonalcoholic fatty liver disease (NAFLD) and chronic kidney disease are global public health issues associated with high morbidity and mortality. Both diseases are also interlinked. Little is known about the meaning of NAFLD in hemodialysis (HD) patients. Therefore, the aim of our study was to investigate the difference in oxidative stress and inflammation in HD patients with or without advanced NAFLD. Seventy-seven HD patients were included (65.14 ± 12.34 years, 59.2% male) and divided according to abdominal ultrasound and two-dimensional shear wave elastography (2D-SWE) measurements into two groups: 1) no NAFLD or no advanced NAFLD (2D-SWE <9 kPa) and 2) advanced NAFLD (2D-SWE ≥9 kPa). Medical history data and blood results were collected. HD patients with advanced NAFLD had significantly higher levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG; p = 0.025), tumor necrosis factor-alpha (TNF-α; p = 0.023), and intercellular adhesion molecule 1 (ICAM-1; p = 0.015) in comparison to HD patients without advanced NAFLD. Interleukin 6 (IL-6) was higher in the advanced NAFLD group, but the difference was of borderline significance (p = 0.054). There was no significant difference in high-sensitivity C-reactive protein (hs-CRP), and vascular cell adhesion molecule 1 (VCAM-1) between groups. In binary logistic regression analysis, advanced NAFLD was significantly associated with 8-OHdG and ICAM-1. In conclusion, higher oxidative stress and inflammation levels are present in HD patients with advanced NAFLD.

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.

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

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

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

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

Metabolic dysfunction-associated steatotic liver disease (MASLD) is intrinsically linked with widespread metabolic perturbations, including within skeletal muscle. Indeed, MASLD is associated with a range of skeletal muscle abnormalities, including insulin resistance, myosteatosis, and sarcopenia, which all converge on the liver to drive disease progression and adverse patient outcomes. This review explores the mechanistic links between skeletal muscle and MASLD, including the role of abnormal glycemic control, systemic inflammation, and disordered myokine signaling. In turn, we discuss how intrinsic liver pathology can feed back to further exacerbate poor skeletal muscle health. Given the central importance of skeletal muscle in MASLD pathogenesis, it offers clinicians an opportunity to intervene for therapeutic benefit. We, therefore, summarize the role of nutrition and physical activity on skeletal muscle mass, quality, and metabolic function and discuss the knock-on effect this has on the liver. An awareness of these treatment strategies is particularly important in the era of effective pharmacological and surgical weight loss interventions, which can be associated with the development of sarcopenia. Finally, we highlight a number of promising drug agents in the clinical trial pipeline that specifically target skeletal muscle in an attempt to improve metabolic and physical functioning.

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.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) may be as high as 38% in the adult population with potential serious complications, multiple comorbidities and a high socioeconomic burden. However, there is a general lack of awareness and knowledge about MASLD and its progressive stages (metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis). Therefore, MASLD is still far underdiagnosed. The 'Global Research Initiative for Patient Screening on MASH' (GRIPonMASH) consortium focuses on this unmet public health need. GRIPonMASH will help (primary) healthcare providers to implement a patient care pathway, as recommended by multiple scientific societies, to identify patients at risk of severe MASLD and to raise awareness. Furthermore, GRIPonMASH will contribute to a better understanding of the pathophysiology of MASLD and improved identification of diagnostic and prognostic markers to detect individuals at risk.

This is a prospective multicentre observational study in which 10 000 high-risk patients (type 2 diabetes mellitus, obesity, metabolic syndrome or hypertension) will be screened in 10 European countries using at least two non-invasive tests (Fibrosis-4 index and FibroScan). Blood samples and liver biopsy material will be collected and biobanked, and multiomics analyses will be conducted.

The study will be conducted in compliance with this protocol and applicable national and international regulatory requirements. The study initiation package is submitted at the local level. The study protocol has been approved by local medical ethical committees in all 10 participating countries. Results will be made public and published in scientific, peer-reviewed, international journals and at international conferences.

NCT05651724, registration date: 15 Dec 2022.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed fatty liver, is closely associated with insulin resistance, obesity and cardiometabolic risk factors. It is the most common cause of liver cirrhosis and hepatocellular carcinoma and is associated with a significantly increased risk of cardiovascular events. With a global prevalence of 25-35%, it represents a growing socioeconomic burden. The diagnosis of MASLD is based on imaging evidence of liver steatosis and clinical criteria of cardiometabolic risk. In the extended diagnostic workup, noninvasive procedures are increasingly replacing liver biopsy for the assessment of liver fibrosis and proper risk stratification. Therapeutic management is based on lifestyle interventions to reduce weight, with studies also demonstrating positive liver effects of glucagon-like peptide‑1 (GLP-1) agonists as well as bariatric surgery. Specific drugs for the treatment of steatohepatitis (MASH) are currently in the approval process.

Obesity is a major risk factor for metabolic-associated steatotic liver disease (MASLD), which can progress to metabolic-associated steatohepatitis (MASH). There are no validated non-invasive tests to stratify persons with obesity with a greater risk for MASH. Herein, we assess plasma and liver from 266 obese individuals spanning the MASLD spectrum. Ninety-six human livers were precision-cut, and mass spectrometry-based proteomics identifies 3,333 proteins in the liver-secretion medium, of which 107 are differentially secreted in MASH compared with no pathology. The plasma proteome is markedly remodeled in MASH but is not different between patients with steatosis and no pathology. The APASHA model, comprising plasma apolipoprotein F (APOF), proprotein convertase subtilisin/kexin type 9 (PCSK9), afamin (AFM), S100 calcium-binding protein A6 (S100A6), HbA1c, and zinc-alpha-2-glycoprotein (AZGP1), stratifies MASH (area under receiver operating characteristic [AUROC] = 0.88). Our investigations detail the evolution of liver-secreted and plasma proteins with MASLD progression, providing a rich resource defining human liver-secreted proteins and creating a predictive model to stratify patients with obesity at risk of MASH.

Estimated remnant cholesterol (Rem-C) level, a risk factor for cardiovascular disease, is associated with metabolic dysfunction-associated steatotic liver disease (MASLD) diagnosed via ultrasonography. However, the relationship between accurate serum Rem-C level measurements and histological findings of MASLD remains unclear.

We aimed to elucidate the relationship between accurately measured serum Rem-C levels and histological findings of MASLD.

Cross-sectional single-center observational study.

We assessed 222 patients (94 men and 128 women; age 20-80) who were diagnosed with MASLD via liver biopsy with available medical history, physical examination, and biochemical measurement data. Serum ester-type cholesterol and free cholesterol contents in the remnant lipoproteins were measured using an enzymatic method.

Serum Rem-C levels were significantly higher in patients with NAFLD activity score (NAS) 5 to 8, >66% steatosis grade, lobular inflammation with ≥5 foci, and many cells/prominent ballooning cells (a contiguous patch of hepatocytes showing prominent ballooning injury) than in patients with NAS 1 to 4, < 33% steatosis grade, lobular inflammation with <2 foci, and few ballooning cells (several scattered balloon cells), respectively. While univariate analysis revealed no significant association between Rem-C levels and advanced fibrosis, a significant association between Rem-C levels and NAS was evident. This relationship remained significant in multivariate analysis adjusted for confounders. Furthermore, in the analysis by sex, these relationships were significant for men but not for women.

High serum Rem-C levels were associated with high NAS but not with fibrosis stage, particularly in men. Controlling serum Rem-C level may improve MASLD activity.

This study investigated the impact of anti-aging protein α-Klotho on cardiometabolic diseases (CMDs) among middle-aged and elderly population. A total of 11,198 participants aged 40-79 years were included in the National Health and Nutrition Examination Survey (NHANES) spanning 2007-2016. Serum α-Klotho levels were quantified via enzyme-linked immunosorbent assays. CMDs comprised cardiovascular disease (CVD), and four metabolic disorders: type 2 diabetes (T2DM), obesity, chronic kidney disease (CKD), and non-alcoholic fatty liver disease (NAFLD). Weighted logistic regression analysis, subgroup analysis, mediation analysis, restricted cubic splines (RCS), and Cox proportional hazards regression analysis were used. α-Klotho exhibited negative associations with each single CMD except T2DM, and RCS showed U-shape and L-shape dose-response relationships of α-Klotho with risk of T2DM and CKD, respectively. Ordered logistic regression analysis revealed that higher levels of Klotho markedly reduced the cumulative number of metabolic comorbidities complicating CVD (OR 0.56 (0.35, 0.91)). Simple mediation analysis showed CKD may explain up to 20.42% of the association between Klotho and CVD. Notably, α-Klotho's association with cardiometabolic comorbidities was particularly evident among individuals who were widowed/divorced/separated, non-Hispanic Black, lower-income, or less educated, with hypertension, current smokers, lower leisure and commuting physical activity, but higher work-related physical activity. Regarding long-term effects, higher α-Klotho levels were associated with lower all-cause mortality among participants with CMDs, but not among those without CMDs. Higher α-Klotho levels were associated with lower CMD prevalence, particularly in high-risk cardiovascular populations with lower socioeconomic status and unfavorable lifestyles and reduced all-cause mortality risk among CMD patients.

Non-alcoholic fatty liver disease (MASLD) is one of the highly prevalent metabolic disorders worldwide The present study aimed to determine the association between a novel dietary lipophilic index (LI) with metabolic profile and MASLD in a population-based study in Amol, Iran.

A cross-sectional study was conducted among 2979 Iranian adults within the framework of the Amol cohort study (AmolCS) Dietary assessments were performed using a validated 168-item food frequency questionnaire (FFQ) The dietary fatty acids were determined using the food composition table in Food Data Central of the USDA to indicate the lipophilic index Information about the melting point of fatty acids was obtained from the lipid bank database MASLD was defined as the ultrasound detection of hepatic steatosis that ruled out other causes of hepatic fat accumulation Then, dietary LI and lipophilic load (LL) were calculated using dietary fatty acid intake and melting point Multivariate MASLD The analysis was carried out for all participants stratified by sex and BMI Potential confounders were included in three different adjusted models.

The results revealed that dietary LI was associated with higher BMI and (WHtR), low physical activity, being female, living in urban residencies, and diabetes After adjustment for potential confounders, age, and energy intake, the odds ratio of MASLD in women was 1.33 (95 % CI: 1.05-1.99, p = 0.048) in the last tertile of dietary LI compared to the first tertile In adjustment by age and energy intake, chronic disease, smoking, physical activity, waist circumference, and residency women have a higher chance of MASLD in the second tertile of dietary LI (OR:1.38 95 % CI: 1.01-1.89) as well as in the third LI (OR:1.39, 95 % CI: 1.02-1.91) compared to the first tertile When the body mass index (BMI) was added to other confounders variables, the odds ratio of MASLD was 1.44 (95 % CI: 1.05-1.99) in the second tertile of LI and 1.41(95 % CI:1.02-1.95) in the third tertiles, Ptrend=0.04 In normal weight participants (BMI< 25), after adjustment for age and energy intake, the odds of MASLD were 86 % higher (CI; 1.07-3.25, Ptrend< 0.03) in the last tertile of LL compared to the first one.

This study found that higher levels of dietary fatty acids are associated with 40 % higher odds of MASLD in women Additionally, higher levels of fatty acids in normal-weight individuals were linked to an 86 % higher chance of MASLD It is highly recommended to reduce intake of saturated fatty acids and trans fatty acids, which are associated with a lower risk of MASLD.

To assess the performance of fibrosis-4 index (FIB-4), nonalcoholic fatty liver disease fibrosis score (NFS) and aspartate aminotransferase to platelet ratio index (APRI) for advanced fibrosis in metabolic dysfunction-associated fatty liver disease (MAFLD) subgroups categorized by concomitant liver conditions.

We conducted a multicentered study comprising inpatients with type 2 diabetes mellitus and MAFLD. Participants were categorized into 2 groups: MAFLD with pure metabolic etiologies (MAFLD-P) and MAFLD with mixed etiologies (MAFLD-M). Diagnostic performance of FIB-4, NFS, and APRI was assessed by area under the curve (AUC), sensitivity, and specificity.

This study comprised a total of 1475 participants, with a mean (SD) age of 58.4 (13) years and 835 (56.6%) males. FIB-4 and APRI had higher AUCs for advanced fibrosis in the MAFLD-M group than in the MAFLD-P group (MAFLD-M vs MAFLD-P: FIB-4 0.680 vs 0.591, P = .0442; APRI 0.723 vs 0.631, P = .0363). No significant difference was observed in the AUC of NFS between the 2 subgroups (MAFLD-M 0.572 vs MAFLD-P 0.617; P = .3237). Besides, the sensitivity of FIB-4 (69.6% vs 54.0%; P = .019) and APRI (43.5% vs 26.1%; P = .005) was higher in the MAFLD-M group. However, no significant difference in sensitivity of NFS and specificity of FIB-4, NFS, and APRI was observed between subgroups.

In this diagnostic study of the type 2 diabetes mellitus population, FIB-4 and APRI showed better performance for identifying advanced fibrosis in MAFLD with mixed etiologies.

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.

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

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.

The relationship between biopsy-proven liver fibrosis progression and renal function decline in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) has not been fully elucidated. We used an automated quantitative liver fibrosis assessment (qFibrosis) technique to investigate the temporal changes in regional liver fibrosis.

This retrospective longitudinal study included 68 MASLD patients and their paired formalin-fixed sections of liver biopsies. One hundred eighty-four fibrosis parameters were quantified in five different hepatic regions, including portal tract, peri-portal, zone 2, peri-central and central vein regions, and qFibrosis continuous values were calculated for all samples based on 10 fibrosis parameters using qFibrosis assessment. Liver fibrosis progression (QLF+, n = 18) and regression (QLF-, n = 23) was defined as at least a 20% relative change in qFibrosis over a 23-month follow-up. Renal function decline was assessed by estimated glomerular filtration rate (eGFR) changes.

The eGFR decline was greater in the QLF+ group (106.53 ± 13.71 ml/min/1.73 m2 vs. 105.28 ± 12.46 ml/min/1.73 m2) than in the QLF- group (110.87 ± 14.58 ml/min/1.73 m2 vs. 114.18 ± 14.81 ml/min/1.73 m2). In addition, liver fibrosis changes in the central vein and pericentral regions were more strongly associated with eGFR decline than in periportal, zone 2 and portal tract regions. We combined these parameters to construct a prediction model, which better differentiated eGFR decline (a cut-off value of qFibrosis combined index = 0.52, p <0.001).

A decline in renal function is significantly related to liver fibrosis progression in MASLD. Regional qFibrosis assessment may efficiently predict eGFR decline, thus highlighting the importance of assessing renal function in patients with MASLD with worsening liver fibrosis.

The study shows that liver fibrosis progression assessed by qFibrosis may be associated with renal function decline, which provides a new perspective for understanding complex pathological processes. A combination of artificial intelligence and digital pathology may earlier and more precisely quantify the progression of regional liver fibrosis, thus better identifying changes in renal function. This opens the possibility of early interventions, which are essential to improve patients' outcomes.

Outcome benefits for HMG-CoA reductase inhibitor (statin) use in the prevention of atherosclerotic cardiovascular disease (ASCVD) are well established and yet, statins remain underutilized with only half of eligible individuals receiving them among certain vulnerable populations. This review critically examines available data to provide a summary of the current evidence for statin use in select populations.

Lipid management can be more complex in patients with chronic kidney disease (CKD), organ transplants, metabolic dysfunction associated with steatotic liver disease (MASLD), and human immunodeficiency virus (HIV). Statins are generally safe and effective to reduce the burden of ASCVD among these highly heterogeneous groups of patients and should be considered with careful attention to their concomitant disease state. Herein, we focus on appropriate statin use in these challenging to treat conditions, their relationship with increased ASCVD risk, and approaches to statin use for ASCVD risk reduction. Although further research is needed to define optimal therapy in select high risk groups for ASCVD prevention, statins are proven to be clinically efficacious, safe, and cost-effective for ASCVD prevention, warranting greater efforts to increase their use.

We aimed to assess the efficacy and safety of Aldafermin in treating patients with biopsy-confirmed metabolic dysfunction-associated steatohepatitis (MASH).

We searched PubMed, Embase, and Cochrane Library for randomized controlled trials (RCTs) comparing Aldafermin to placebo for treating patients with MASH up to December 8, 2024. The risk ratios (RR) with 95 % confidence intervals (CI) were pooled for binary outcomes using a random-effects model. Additionally, we conducted subgroup analysis by fibrosis stage and Aldafermin dosage, and meta-regression analysis assuming the dosage of Aldafermin as a covariate.

We included 4 RCTs, encompassing 491 patients. Compared to placebo, Aldafermin had a higher probability of MASH resolution without worsening of fibrosis (RR 3.04; 95 %CI 1.12-8.28), composite of fibrosis improvement and MASH resolution (RR 5.86; 95 %CI 1.15-29.94), and reduction ≥30 % in hepatic fat fraction by MRI-PDFF (RR 3.14; 95 %CI 1.44-6.85). There were no significant differences in fibrosis improvement ≥1 stage without worsening of MASH (RR 1.48; 95 %CI 0.93-2.35), and overall AEs (RR 1.02; 95 %CI 0.95-1.11) between the groups. Subgroup analysis by fibrosis stage and Aldafermin dosage showed consistent results, and meta-regression analysis by dosage showed a dose-dependent improvement for the outcome of ≥30 % reduction in hepatic fat fraction by MRI-PDFF.

In conclusion, Aldafermin improved MASH resolution without worsening fibrosis, enhanced the composite of fibrosis improvement and MASH resolution, reduced hepatic fat fraction by MRI-PDFF, and was safe for treating patients with biopsy-confirmed MASH compared to placebo.

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

Identifying metabolic dysfunction-associated steatotic liver disease (MASLD) patients at increased risk of cardiovascular mortality remains an unmet clinical need. We investigated the ability of four systemic inflammation markers to identify cardiovascular mortality risk in MASLD patients.

This cohort study included 4787 MASLD patients from the National Health and Nutrition Examination Survey (NHANES) from 2005 through 2018. The weighted Cox proportional hazards model was used to assess the relationship between four systemic indicators of inflammation and cardiovascular mortality. During a median (IQR) follow-up of 7.0 (3.8-10.3) years, 567 all-cause mortality and 174 cardiovascular mortality were recorded. Compared to the first quartile of systemic inflammation levels, the HRs of cardiovascular mortality in the fourth quartile were 3.22 (95 % CI 1.83-5.66) for SII, 2.74 (95 % CI 1.32-5.69) for SIRI, 3.69 (95 % CI 1.87-7.28) for NLR, and 1.83 (95 % CI 1.05-3.20) for PLR. For predicting 10-year cardiovascular mortality, SIRI (AUC = 0.70) and NLR (AUC = 0.69) were superior to SII (AUC = 0.60) and PLR (AUC = 0.52). Stratification of MASLD patients based on the optimal cutoff values revealed an HR of 2.67 (95 % CI 1.65-4.32) for cardiovascular mortality with SIRI > 1.23, and an HR of 2.39 (95 % CI 1.51-3.79) with NLR > 2.18. Combining systemic inflammation markers with the Fibrosis-4 Score can provide more accurate prognostic information for MASLD patients.

SIRI and NLR outperformed SII and PLR in predicting the risk of cardiovascular mortality, proving to be useful tools for risk stratification in MASLD patients.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is common in obesity. Guidelines recommend liver fibrosis risk stratification with tools such as Fibrosis-4 (FIB-4) index, liver stiffness measurement with vibration-controlled transient elastography (VCTE) and/or hepatology referral for elevated FIB-4. Despite recommendations, implementation remains limited. Using mixed methods, we evaluated a three-strategy implementation bundle to improve fibrosis risk stratification-a FIB-4-based electronic health record embedded clinical decision support system (CDSS), educational outreach, and internal facilitation in a weight management clinic.

The primary outcome was penetration: the proportion of patients with elevated FIB-4 completing VCTE or hepatology referral. We compared rates, pre and post activation of implementation bundle using Fischer's exact test. Semi-structured provider interviews, guided by the i-PARIHS framework, assessed acceptability and feasibility three months post-implementation.

In the pre-activation phase, 880/3933 (22.4%) weight management visits had the necessary labs to calculate automated FIB-4 scores with 128 elevated scores. In the post-activation phase, 2513/4,634 weight management visits (54.2%) had automated FIB-4 scores; with 234 elevated score. Pre-activation, there were no VCTE and 2 hepatology referrals. Post-activation, there were 3 VCTE referrals and 2 hepatology referrals (Fischer's exact test p-value=1.00). Providers cited shared responsibility with primary care, low awareness and trust in risk-stratification tools, workflow challenges, and competing demands as barriers. Educational outreach and facilitation improved CDSS engagement, while technical issues reduced it.

This implementation strategy bundle did not achieve meaningful MASLD fibrosis risk stratification. EHR based CDSS shows promise but requires alignment with provider priorities, seamless workflow integration, and robust technical infrastructure.

The development of accurate noninvasive tests to identify individuals with metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis is of great clinical importance. In this study, we aimed to develop 2 noninvasive diagnostic models on the basis of routine clinical and laboratory data, using machine learning, to identify patients with MASH and significant fibrosis (fibrosis stages 2 to 4), respectively.

This analysis included the training (n=456) and the validation (n=105) sets of patients who underwent liver biopsy and laboratory testing for liver disease at 2 hospitals in China. Logistic regression, random forest, support vector machine, and the XGBoost algorithm were used to construct models, respectively. The best diagnostic models for MASH and significant fibrosis were compared with 7 existing noninvasive scoring systems including AAR, AST to platelet ratio index (APRI), BARD score, fibrosis-4 (FIB-4), fibrotic non-alcoholic steatohepatitis (NASH) index (FNI), homeostatic model assessment of insulin resistance (HOMA-IR), and non-alcoholic fatty liver disease fibrosis score (NFS). Performance was estimated by the area under the receiver operating characteristic curve (AUROC).

The final noninvasive diagnostic model integrated 19 indicators derived from routine clinical and laboratory tests. The XGBoost models exhibited superior performance in MASH and significant fibrosis with an improved AUROC value (MASH, 0.670, 95% CI 0.530-0.811; significant fibrosis, 0.713, 95% CI 0.611-0.815) compared with other noninvasive scoring systems in the validation set.

Utilizing machine learning can assist in diagnosing MASH and significant fibrosis based on clinical epidemiological information with good diagnostic performance.

BackgroundThe mechanisms underlying the occurrence and progression of metabolic dysfunction-associated steatohepatitis (MASH)-related liver fibrosis remains poorly understood. This study aims to identify key transcription factors involved in the development of liver fibrosis in MASH patients, thereby providing potential targets for drug discovery.MethodsMicroarray data were retrieved from liver biopsy specimens of MASH patients exhibiting varying stages of fibrosis via the Gene Expression Omnibus database. Differentially expressed transcription factors (DETFs) were identified through the application of Weighted Gene Co-expression Network Analysis. A set of in vitro and in vivo experiments were conducted to investigate the role of MEOX1 in MASH-related fibrosis. To delineate the potential mechanisms, the transcriptomic RNA sequencing (RNA-seq), Alphafold, and PyMOL were used.ResultsA total of six DETFs (MEOX1, SOX4, LEF1, SOX9, MYC, and CBX2) were identified as being positively correlated with the progression of MASH-related fibrosis. MEOX1 was increased in mouse model of MASH diet-induced liver fibrosis and hepatic stellate cells (HSCs) stimulated by transforming growth factor-β1. Knockdown of the MEOX1 markedly suppressed the activation, proliferation, and migration of HSCs. RNA-Seq analysis identified serine protease inhibitor family E member 1 (SERPINE1) as the critical target of MEOX1 within HSCs. The protein interaction sites of MEOX1 and SERPINE1 were predicted using Alphafold and PyMOL.ConclusionIn summary, as a pivotal transcription factor, MEOX1 activates HSCs via SERPINE1, thereby promoting liver fibrosis associated with MASH. Inhibition of the MEOX1-SERPINE1 pathway could offer a novel therapeutic avenue for treating MASH-related fibrosis.

Low physical activity has been shown to be associated with higher risk of non-alcoholic fatty liver disease (NAFLD). However, the strength and shape of this association are currently uncertain due to a reliance on self-reported physical activity measures. This report aims to investigate the relationship of median daily step count with NAFLD using accelerometer-derived step count from a large prospective cohort study.

The wrist-worn accelerometer sub-study of the UK Biobank (N = ~100,000) was used to characterise median daily step count over a seven-day period. NAFLD cases were ascertained via record linkage with hospital inpatient data and death registers or by using a measure of liver fat from imaging. Cox proportional hazards models were employed to assess the association between step count and NAFLD, adjusting for age, sociodemographic, and lifestyle factors. Mediation analyses were conducted.

Among 91,031 participants (709,440 person-years of follow-up), there were 762 incident NAFLD cases. Higher step count was log-linearly and inversely associated with risk of NAFLD. A 1000-step increase (representing 10 minutes of walking) was associated with a 12% (95% CI: 10%-14%) lower hazard of NAFLD. When using imaging to identify NAFLD, a 1,000-step increase was associated with a 6% (95% CI: 6%-7%) lower risk. There was evidence for mediation by adiposity, accounting for 39% of the observed association.

Daily step count, a modifiable risk factor, is log-linearly and inversely associated with NAFLD. This association was only partially explained by adiposity. These findings from a large cohort study may have important implications for strategies to lower NAFLD risk.

Studies have demonstrated that both lower limb arterial calcification and metabolic dysfunction-associated steatotic liver disease (MASLD) are linked to the development of peripheral artery disease. However, the potential relationship between MASLD biomarkers and progression of lower limb arterial calcification in individuals with type 2 diabetes (T2D) remains unclear. This study aimed to investigate whether the biomarkers of MASLD included in the FibroMax® panels are associated with the progression of lower limb arterial calcification in patients with T2D.

The lower limb arterial calcification score (LLACS) was evaluated through computed tomography at baseline and after an average follow-up of 31.2 ± 3.7 months in a cohort of 150 patients with T2D. We also measured the serum biomarkers included in the FibroMax® panels (SteatoTest®, FibroTest®, NashTest®, ActiTest®). The predictive ability of these biomarkers of MASLD on LLACS progression was assessed through univariate and multivariate linear regression models, principal component regression analysis, as well as machine learning algorithms.

During the follow-up period, LLACS increased in 127 (85%) of the 150 patients with T2D. In univariate analysis, the annualized change in LLACS was positively and mainly correlated with baseline LLACS (r = 0.860, p < 0.0001), the FibroTest® score (r = 0.304, p = 0.0002), and age (r = 0.275, p = 0.0006), and negatively correlated with glomerular filtration rate (r = - 0.242, p = 0.003). In multivariate analysis, the FibroTest® score remained independently associated with the annualized change in LLACS, after adjusting for baseline LLACS and risk factors for lower extremity artery disease (β coefficient [95% confidence interval]: 988 [284-1692], p = 0.006). This association persisted even after adjustment for variables selected by principal component analysis (β = 1029 [289-1768], p = 0.007). Two advanced machine learning models identified the FibroTest® score as the second most important predictor of annualized change in LLACS, following baseline LLACS.

This study represents the first demonstration of an independent relationship between a non-invasive liver fibrosis test and the progression of lower limb arterial calcification in patients with T2D. Beyond its utility in assessing liver fibrosis, the FibroTest® could be a valuable and easy-to-use biomarker for predicting the risk of worsening lower limb arterial calcification.

ClinicalTrials.gov identifier NCT02431234.

Macrophages hold a critical position in maintenance of hepatic homeostasis and in injury and repair processes in acute and chronic liver diseases. TIM3 is a promising protector in MCD-induced steatohepatitis in acute liver injury. However, we recently find TIM3 as a driver of fibrosis in MCD/HFD-induced chronic liver injury. This study aims to explore how macrophage TIM3 drivers NAFLD-associated chronic liver injury as well as identify a subtype of fibrotic patients suitable for anti-TIM3 immunotherapy. Here, we found that TIM3 was highly expressed in liver macrophages in a long-term MCD- or HFD-fed mice with fibrotic NASH. Elevated β-TrCP in macrophages promoted TIM3 polyubiquitination and membrane translocation. The ubiquitinated TIM3 then bound with PI3K and followed by inhibition of mTOR and activation of macrophage M2 polarization and TGF-β release, leading to HSC activation and liver fibrosis. Furthermore, elevated TIM3 was attributed to the transcriptional TBP upregulation and miR-4524a-5p downregulation. Targeting of TIM3 significantly attenuated liver fibrosis in mice. In clinical NASH patients, elevated macrophage TIM3 is positively correlated with TBP expression and negatively associated with miR-4524a-5p. Decreased miR-4524a-5p in plasma was a biomarker for the NASH fibrosis patients suitable for anti-TIM3 therapy. In conclusion, this study reveals that miR-4524a-5p/TBP promotes β-TrCP/TIM3 complex activation in macrophages and aggravates chronic NASH fibrosis, providing miR-4524a-5p as an effective blood biomarker for a subtype of chronic NASH patients with fibrosis suitable for anti-TIM3 treatment.

Insulin resistance (IR) is a crucial mechanism in the pathogenesis and clinical progression of metabolic dysfunction-associated steatotic liver disease (MASLD). This study aimed to examine the relationship between non-insulin-based IR surrogate markers and the incidence of liver-related outcomes in individuals with MASLD in a nationwide Korean cohort.

A total of 66,334 individuals with MASLD who underwent a health examination between 1 January 2009 and 31 December 2010 were included in the study and followed until 31 December 2019, with a median follow-up period of 9.4 years. Hepatic steatosis was defined as a fatty liver index ≥ 30. The triglyceride-glucose (TyG) index, triglyceride-to-high-density lipoprotein cholesterol (TG/HDL) ratio, and metabolic score of IR (METS-IR) were employed as non-insulin-based IR surrogate markers. The MASLD groups were divided into four groups based on the non-insulin-based IR surrogate markers quartiles. The primary outcome was liver-related outcomes, as a composite of hepatocellular carcinoma and decompensated liver cirrhosis.

The MASLD group was 64.4% male (average age, 59.0 years). Using the lowest quartile (Q1) of the three non-insulin-based IR surrogate markers as a reference, a decrease in the adjusted hazard ratio for liver-related outcomes was observed from Q2 to Q4: (TyG: Q2 0.90 [95% confidence interval [CI]: 0.79-1.02], Q3 0.80 [95% CI: 0.70-0.91], Q4 0.80 [95% CI: 0.69-0.92]; TG/HDL: Q2 0.85 [95% CI: 0.75-0.97], Q3 0.81 [95% CI: 0.71-0.92], Q4 0.81 [95% CI: 0.71-0.93]; METS-IR: Q2 0.83 [95% CI: 0.73-0.95], Q3 0.80 [95% CI: 0.70-0.91], Q4 0.80 [95% CI: 0.70-0.92]).

A lower non-insulin-based IR surrogate marker in the MASLD group may be associated with an increased risk of liver-related outcomes. In the course of monitoring MASLD, metabolic alterations must be meticulously observed.

Hepatic stellate cells (HSCs) are non-parenchymal cells of the liver that produce the extracellular matrix that forms fibrotic lesions in chronic liver disease, including metabolic dysfunction-associated steatohepatitis (MASH). The mitochondrial pyruvate carrier (MPC) catalyzes the transport of pyruvate from the cytosol into the mitochondrial matrix, which is a critical step in pyruvate metabolism. An MPC inhibitor has shown promise as a novel therapeutic for MASH and HSC activation, but a mechanistic understanding of the direct effects of MPC inhibition on HSC activation is lacking.

Stable lines of LX2 cells expressing short hairpin RNA against MPC2 were established and examined in a series of studies to assess HSC metabolism and activation. Mice with conditional, HSC-specific MPC2 deletion were generated and their phenotypes assessed in the context of diets that cause hepatic steatosis, injury, and early-stage fibrosis.

Genetic suppression of MPC activity markedly decreased expression of markers of HSC activation in vitro. MPC knockdown reduced the abundance of several intermediates of the tricarboxylic acid cycle and attenuated HSC activation by suppressing hypoxia inducible factor-1α signaling. Supplementing alpha-ketoglutarate to replenish the tricarboxylic acid cycle intermediates was sufficient to overcome the effects of MPC inhibition on hypoxia inducible factor-1α and HSC activation. On high-fat diets, mice with HSC-specific MPC deletion exhibited reduced circulating transaminases, numbers of HSCs, and hepatic expression of markers of HSC activation and inflammation compared with wild-type mice.

These data suggest that MPC inhibition modulates HSC metabolism to attenuate activation and illuminate mechanisms by which MPC inhibitors could prove therapeutically beneficial for treating MASH.

Metabolic hepatic steatosis (MetHS) is a clinically heterogeneous, multisystemic, dynamic, and complex disease, whose progression is one of the main causes of cirrhosis and hepatocarcinoma. This clinical practice guideline aims to respond to its main challenges, both in terms of disease burden and complexity. To this end, recommendations have been proposed to experts through the Delphi method. The consensus was optimal in recommendations regarding type 2 diabetes as a risk factor (1.5.1, 4.5.1), in which cases early detection of MetHS should be carried out (4.5.2). Its results also emphasize the importance of the use of non-invasive tests (FIB-4, NFS, HFS) for the exclusion of significant fibrosis in patients with suspected MetHS (2.3.1, 2.3.3). Diagnosis should be carried out through the sequential combination of non-invasive indices and transient elastography by FibroScan® for its risk stratification (2.3.3). A nearly unanimous consensus was reached regarding the role of early prevention in the impact on the quality of life and survival of patients (5.1.2), as well as on the effectiveness of the Mediterranean diet and physical exercise in relation to the improvement of steatosis, steatohepatitis and fibrosis in MetHS patients (5.2.2) and on the positive results offered by resmiterom and semaglutide in promoting fibrosis regression (5.4.1). Finally, a great consensus has been reached regarding the importance of multidisciplinary management in MetHS, for which it is essential to agree on multidisciplinary protocols for referral between levels in each health area (6.2.1), as well as ensuring that referrals to Hepatology/Digestive and Endocrinology or Internal Medicine services are effective and beneficial to prevent the risk of disease progression (6.2.3, 6.3.1).

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

Fibrosis is the pathological outcome of many chronic inflammatory diseases, affecting various human organs. It is a significant contributor to global morbidity and mortality that affects nearly half of the elderly population. Pirfenidone (PFD) and nintedanib are approved by the FDA for treating pulmonary fibrosis, but these treatments are associated with poor tolerability and limited efficacy. Moreover, no antifibrotic drugs are approved for other fibrosis-related diseases, highlighting an urgent unmet medical need for more effective therapies. Here we report the in vivo pharmacological activities of AK3280, a novel, orally bioavailable small molecule designed to enhance pharmacokinetics, antifibrotic activity, and tolerability over PFD. AK3280 demonstrated antifibrotic effects across multiple organs, including the lungs, liver, heart, and skin, in various animal models. These results suggest that AK3280 holds promise as a clinically beneficial antifibrotic therapy for a range of fibrotic diseases, especially pulmonary, hepatic, cardiac, and skin fibrosis.

The classification of steatotic liver disease (SLD) has evolved, incorporating all conditions characterized by hepatic lipid accumulation. SLD represents a continuum of disorders that are shaped by the dynamic factors of alcohol intake and cardiometabolic risk factors. This updated classification has profound implications for both the management and research of SLD, especially with the new distinct category of patients with both metabolic and alcohol-related liver disease. In this Perspective, we highlight the pivotal role of alcohol within the SLD framework. We introduce the 'SLD burden paradox': a concept illustrating the disparity in which metabolic dysfunction-associated steatotic liver disease is more prevalent, yet individuals with SLD and excessive alcohol intake (such as in metabolic and alcohol-related liver disease and in alcohol-related liver disease) account for greater global liver-related morbidity and mortality. We explore strategies to mitigate the effect of SLD on morbidity and mortality, emphasizing the importance of early detection and reducing stigma associated with alcohol intake. Our discussion extends to methods for assessing and monitoring alcohol intake together with the critical role of managing cardiometabolic risk factors in patients across the SLD spectrum. Conclusively, we advocate for a coordinated care framework that adopts a person-centric approach when managing SLD, aiming to improve outcomes and patient care.

The prognostic importance of changes in vibration-controlled transient elastography (VCTE) parameters, liver stiffness measurement (LSM), and controlled attenuation parameter (CAP), in individuals with type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD) is unknown.

A prospective cohort of 288 patients underwent 2 VCTE exams at least 2 years apart, and the relative percentage changes in LSM and CAP were calculated. Outcomes were the occurrence of any liver-related events (LREs), cardiovascular events (CVEs), and all-cause mortality. Multivariable Cox analyses, adjusted for liver and cardiometabolic factors, assessed associations between VCTE parameters changes, both as continuous and dichotomical variables (LSM increase >15% and CAP reduction >10%), and outcomes.

During a median follow-up of 6 years, there were 22 LREs, 28 CVEs, and 37 all-cause deaths. For LREs, baseline LSM was the strongest predictor, but LSM increases added further prognostic value (hazard ratio [HR]: 1.5 [1.0-2.1], 1-SD increment). For CVEs, both LSM increase (HR: 1.7 [1.3-2.3]) and CAP reduction (HR: 1.5 [1.0-2.3], 1-SD decrease) were significant predictors. For all-cause mortality, baseline CAP was a protective predictor. When classified into subgroups based on LSM and CAP changes, the subgroup with both increased LSM and reduced CAP had the highest risks for CVEs (HR:5.3 [1.4-19.6]) and all-cause mortality (HR: 3.4 [1.2-9.6]). The highest risk for LREs was observed in the subgroup with increased LSM without CAP reduction (HR: 3.5 [0.9-12.9]).

VCTE parameters changes, LSM increase and CAP reduction, provide prognostic information for adverse liver, cardiovascular, and mortality outcomes in individuals with T2D and MASLD.

The nonalcoholic steatohepatitis clinical research network (NASH-CRN) system is commonly used for histologic assessment of disease activity and fibrosis in NASH. Despite this, the system does not fully capture the range of disease activity and fibrosis. As such, an expanded NAS (E-NAS) grading and staging system with a calculated E-NAS index was developed by our group. In this follow up study, we aim to revalidate the E-NAS system and compare its reliability to existing systems. Hematoxylin and eosin and trichrome stained sections from 40 liver biopsies were reviewed digitally by four hepatopathologists and assessed using the NASH-CRN and E-NAS systems as well as a modified Ishak fibrosis stage. The pathologist's gestalt impression of disease activity and fibrosis was scored on a Visual Analogue Scale (VAS), which ranged from 0 (no activity/fibrosis) to 100 (the worst activity/fibrosis ever seen). Inter-rater reliability was assessed, and Spearman correlation coefficients were calculated. The E-NAS index had higher inter-rater agreement versus the NAS score (ICC 0.70 vs 0.61). The inter-rater agreement for ballooning in the E-NAS system was also higher at 0.67 compared to the NAS (ICC 0.60). ICCs for fibrosis were comparable between all the systems assessed (0.78 to 0.88). Finally, the calculated E-NAS index was higher with increasing stage of fibrosis compared to the NAS suggesting that it associates better with fibrosis. In summary, the E-NAS system demonstrates substantial inter-rater reliability as well as improved correlation with disease activity VAS and fibrosis compared to the NAS score.

Despite the heavy individual patient and socioeconomic burden of metabolic dysfunction-associated steatohepatitis (MASH), until recently, no pharmacological therapy for MASH was approved, with available treatment options geared towards associated cardiometabolic risk factors. Accelerated approval of resmetirom, a thyroid hormone receptor-β agonist to be used in conjunction with diet and exercise, marks a significant step forward in the treatment of MASH, offering tempered optimism to healthcare providers and millions of patients around the world for more effective management. Evidence from phase 2 and 3 clinical trials suggests that resmetirom has the potential to alleviate hepatic fibrosis and inflammation and significantly reduce liver lipid content. Notwithstanding this landmark event, the clinical implementation of resmetirom comes with important challenges, for example, ensuring patient access to treatment and demonstrating effects on hard MASH-related outcomes, such as progression to cirrhosis and hepatocellular carcinoma. Additional considerations include the evaluation of co-administration with other hepatoprotective treatments and the assessment of the efficacy in specific MASH sub-phenotypes. Furthermore, the accumulation of real-world data and experience is expected to help answer the remaining questions about the (long-term) effectiveness and safety profile of the drug. The purpose of this article is to provide an updated and critical review of the mechanisms of action, efficacy, and safety of resmetirom based on the latest clinical trials, to define its place within the broader landscape of MASH management, and to highlight current knowledge gaps and opportunities for future research in the field.