Self-reported health varies across countries, as populations attribute different degrees of value to EQ-5D domains. Country-specific EQ-5D tariffs were developed to account for this but are not always stated in the literature. We aim to assess the reporting of EQ-5D in the literature and the impact of applying country-specific tariffs.

We reviewed literature-reported EQ-5D utilities for patients with metabolic dysfunction-associated steatohepatitis versus real-world EQ-5D utilities from the Adelphi Real World Non-alcoholic steatohepatitis Disease Specific Programme (DSP), a cross-sectional survey in France, Germany, Italy, Spain, the United Kingdom and the United States. Matching-adjusted indirect comparison analysis balanced DSP data with literature studies by age, sex, comorbidities and fibrosis stage. DSP utility scores generated using national tariffs were compared with literature utilities using weighted t tests.

Ten studies with varying recruitment criteria, patient demographics and clinical characteristics were identified. Country-specific tariffs were not used or not reported. EQ-5D utilities varied, reflecting geographic, clinical and demographic characteristics. The comparison of literature and matched utilities derived using DSP data and five national tariffs revealed ≥ two comparisons for each study with a difference not exceeding the minimal clinically important difference versus the matched DSP value.

Literature-reported EQ-5D utilities vary considerably depending on study methodology and country-specific EQ-5D tariff, and even if stated may not always use the most appropriate tariff. This suggests a need for consistent use of country-specific tariffs and sensitivity analyses confirming results and conclusions that include EQ-5D-based utility measurement to inform decision-making by health authorities.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is often regarded in society as a disease caused by personal lifestyle and dietary choices. Healthcare providers who have empathy and are able to explain the disease trajectory can better engage with people with MASLD and actively work with them to improve their metabolic health on a sustainable basis. Non-invasive tests can assist in this process, but healthcare providers must ensure they explain their advantages and limitations. Discussing and setting lifestyle goals are priorities before initiating specific pharmacological treatment, since living a healthy lifestyle will remain the backbone of the multimodal management of MASLD. In this review, we discuss challenges and opportunities to actively engage with people living with MASLD in a multimodal treatment framework as a healthcare provider.

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

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.

To date, an increasing body of evidence supports the potential role of activated platelets in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). This is likely due to their ability to secrete biologically active substances that regulate liver regeneration processes, ensure hemostasis, and participate in the immune response. Additionally, several studies have demonstrated the efficacy of antiplatelet agents in reducing inflammation, the severity of liver fibrosis, and the progression of fibrosis in non-alcoholic steatohepatitis (NASH). Since NAFLD is not an independent indication for antiplatelet therapy, the primary evidence regarding their efficacy in NAFLD has been derived from studies using animal models of NAFLD or in patients with concomitant cardiovascular diseases. This narrative review will discuss the main functions of platelets, their unique interactions with liver cells, and the outcomes of these interactions, as well as the results of studies evaluating the efficacy and safety of antiplatelet therapy in patients with NAFLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of end-stage liver disease. MASLD and liver fibrosis are associated with cardiometabolic risk factors and health-related quality of life (HRQOL) while being affected by dietary/exercise patterns and social determinants of health (SDOH). However, previous studies have not assessed in conjunction exercise, diet, SDOH, and HRQOL in patients with MASLD. This was a cross-sectional study of patients with MASLD seen in hepatology clinic at University of Michigan. Participants completed validated surveys on HRQOL, diet, and physical activity, and a subset also underwent vibration controlled transient elastography (VCTE). The primary outcomes were HRQOL (measured by Short Form-8) and cirrhosis, and predictors were physical activity, dietary patterns, cardiometabolic comorbidities, and social determinants of health. The primary analysis included 304 patients, with median body mass index 32.4 kg/m2 and prevalence of type 2 diabetes, hypertension, and dyslipidemia 38%, 45%, and 42%, respectively (Table 1). The majority of the participants had a FIB-4 score of less than 1.3 and LSM of less than 8 (Table 1). HRQOL was lower with higher BMI, type 2 diabetes, hypertension, and increased liver fibrosis, and higher in people with adequate fruit intake. Neighborhood-level SDOH were also associated with HRQOL. Factors associated with cirrhosis or higher liver stiffness measurement by VCTE included body mass index, diabetes, and living in an impoverished neighborhood, while increased vegetable intake and exercise were associated with lower prevalence of cirrhosis/fibrosis. In multivariable models including demographic and cardiometabolic factors, dietary patterns and SDOH were independently associated with HRQOL and cirrhosis. Cardiometabolic risk factors, physical activity, diet, and social determinants of health are associated with HRQOL and liver fibrosis.

Non-alcoholic steatohepatitis (NASH) is a serious end-stage spectrum of non-alcoholic fatty liver disease (NAFLD) with associated high risk of hepatic and extrahepatic complications. Several studies showed the significant beneficial effect of dapagliflozin on body composition, hepatic and metabolic parameters on NAFLD/NASH patients. The study aimed to investigate the efficacy and safety of dapagliflozin in both diabetic and non-diabetic biopsy-proven NASH patients; compared to pioglitazone.

This was a four-group, prospective, randomized, parallel, open label study in which 100 biopsy-proven NASH patients were selected, stratified to diabetics and non-diabetics and randomized with 1:1 allocation to either 30 mg pioglitazone or 10 mg dapagliflozin, once daily for 24 weeks. Histological evaluation, anthropometric measures, hepatic, metabolic biochemical markers, fibrosis non-invasive markers, quality of life (QOL) and medications adverse events were examined.

Dapagliflozin showed a comparable histological effect to pioglitazone in both diabetic and non-diabetic patients (P>0.05). As assessed by transient elastography, it also showed a comparable effect on liver fibrosis grade improvement from baseline in diabetics (P=0.287) versus a significant superiority in non-diabetics (P=0.018). Dapagliflozin showed a significant superiority in all anthropometric measures (P<0.001) and QOL (P<0.05) among both diabetics and non-diabetics. There was a significant interaction between interventions and diabetes status on change from baseline of hepatic and metabolic panel collectively (P=0.023) in favor to dapagliflozin among diabetics.

Compared to pioglitazone, dapagliflozin had a comparable effect histologically, superior effect biochemically among diabetics and superior effect on liver fibrosis, steatosis and insulin resistance among non-diabetics.

The study was registered on clinicaltrials.gov, identifier number NCT05254626.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dual GLP-1/glucose-dependent insulinotropic peptide (GIP) or glucagon receptor agonists have emerged as promising agents to treat metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH). Although the beneficial effects of GLP-1RAs on glycemic control and weight are well-established, clinicians may be unfamiliar with other potential benefits of this class.

We examined the pleiotropic effects of GLP-1RAs and how they relate to gastroenterologists for MASLD/MASH treatment. Our narrative review of English articles included four GLP-1RAs (subcutaneous semaglutide, liraglutide, dulaglutide, and efpeglenatide), a dual GLP-1/GIP agonist (tirzepatide), a dual GLP-1/glucagon receptor agonist (survodutide), MASLD/MASH, related disorders, clinical management, treatment outcomes and landscape.

In Phase I - III trials, GLP-1RAs are associated with clinically relevant hepatic improvements including MASH resolution, liver fat reduction, and preventing worsening fibrosis. Effects on cardiometabolic parameters align with type 2 diabetes/obesity Phase III data, comprising substantial improvements in glycemic, weight, and cardiovascular outcomes. Promising data also suggest benefits in common comorbidities, including obstructive sleep apnea, polycystic ovary syndrome, chronic kidney disease, and heart failure with preserved ejection fraction.GLP-1RAs represent a valuable pharmacotherapeutic option for gastroenterologists managing individuals with MASLD/MASH and cardiometabolic comorbid conditions.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly becoming more prevalent in the general population. MASLD is more common in persons with low socioeconomic status (SES), yet little is known about the psychosocial challenges associated with this disease, and clinical recommendations on how to approach psychosocial challenges are lacking.

A PubMed search using the search terms MASLD, psychosocial risks, stigmatization, psychiatric comorbidities (i.e. depression, bipolar disorder, psychosis, attention deficit hyperactivity disorder, and substance abuse), SES, quality of life (QoL), over the past 20 years (2004-2024) was performed.

Persons with MASLD often experience psychosocial adversities that may be expressed as lower SES, high prevalence of depression, and reduced QoL. Knowledge gaps remain regarding the association between severe mental disorders (e.g. psychosis and bipolar disorders). Timely detection and treatment of MASLD in persons with psychosocial risks may require attention and cross-field collaboration. Studies on QoL in persons with MASLD differ in methodology which makes formal comparisons difficult. Psychosocial adversity may be a barrier to lifestyle modifications, which remain the cornerstone of MASLD management. Guidelines on how to address psychosocial adversities in a clinical setting are warranted to improve outcomes and decrease further multimorbidity.

Background and Objectives: The pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) remains incompletely understood. However, recent studies highlight the interactions between muscle, liver, and adipose tissue. This study aimed to explore the relationships between clinical indicators of MASLD and sarcopenia, cardiorespiratory fitness, fatigue, and mood. Materials and Methods: The study involved 60 participants, including 28 healthy controls and 32 with MASLD, categorized into two disease subgroups: 15 with MASL and 17 with metabolic dysfunction-associated steatohepatitis (MASH). Participants completed an incremental speed shuttle walk test to evaluate cardiorespiratory fitness, a hand-held dynamometer assessment for appendicular muscle strength, and the timed up and go test for physical performance. Physical activity level, fatigue, quality of life, and emotional state were assessed using questionnaires. The test results were compared between groups and with disease characteristics. Results: MASL and MASH groups showed reduced cardiorespiratory fitness (p < 0.001). The knee extensors were significantly weaker in both MASL and MASH groups (p < 0.001 and p = 0.001, respectively). The MASH group reported higher levels of depression and negative health perception (p = 0.006 and p = 0.03, respectively). Muscle strength in patients with MASLD showed a significant negative association with depression (OR = -0.384, 95% CI: -3.10 to -0.74, p = 0.003), intrahepatic triglyceride content (OR = -0.287, 95% CI: -1.31 to -0.11, p = 0.023), and LDL (OR = -0.286, 95% CI: -0.02 to -0.33, p = 0.03). In contrast, a positive association was observed between VO2 and muscle strength (OR = 0.531, 95% CI 1.27 to 3.47, p < 0.001). Conclusions: This study suggests that muscle strength is linked to key metabolic parameters, such as hepatic fat, LDL levels, and aerobic capacity, that may contribute to the development and progression of MASLD. Interventions aimed at preserving or enhancing muscle strength in MASLD patients may be essential for preventing liver damage and improving metabolic health.

Chronic liver diseases and cirrhosis are associated with mood disorders. Regular exercise has various beneficial effects on multiple organs, including the liver and brain. However, the therapeutic effect of exercise on liver fibrosis concomitant with anxiety has not been evaluated. In this study, the effects of exercise training on liver fibrosis-related anxiety-like behaviors were evaluated. Male C57/BL6 mice were divided into four groups: vehicle-sedentary, vehicle-exercise, carbon tetrachloride (CCl4)-sedentary, and CCl4-exercise. Liver fibrosis was induced by CCl4 administration for 8 wk, exercise was applied in the form of voluntary wheel running. After an intervention, anxiety-like behavior was assessed using the elevated plus maze. CCl4 increased liver and serum fibrotic markers, as measured by blood analysis, histochemistry, and qRT-PCR, and these changes were attenuated by exercise training. CCl4 induced anxiety-like behavior, and the anxiolytic effects of exercise occurred in both healthy and liver-fibrotic mice. In the hippocampus, CCl4-induced changes in neuronal nitric oxide synthase (nNOS) were reversed by exercise, and exercise enhanced brain-derived neurotrophic factor (BDNF) induction, even in a state of severe liver fibrosis. These results suggested that hepatic fibrosis-related anxiety-like behaviors may be induced by excess hippocampal nNOS, and the beneficial effects of exercise could be mediated by increases in BDNF and reductions in nNOS. The percentage of fibrotic area was negatively correlated with antianxiety behavior and positively associated with hippocampal nNOS protein levels. Liver fibrosis-related anxiety-like behaviors could be alleviated through the regulation of hippocampal BDNF and nNOS via exercise training. These results support the therapeutic value of exercise by targeting the mechanisms underlying liver fibrosis and associated anxiety.NEW & NOTEWORTHY This study explores how exercise affects liver fibrosis-related anxiety in mice. Researchers found that regular exercise reversed carbon tetrachloride (CCl4)-induced liver fibrosis and reduced anxiety, even in mice with liver fibrosis. Exercise increased brain-derived neurotrophic factor (BDNF) and decreased neuronal nitric oxide synthase (nNOS) in the hippocampus. These findings suggest that exercise has therapeutic potential for treating anxiety associated with chronic liver disease by modulating specific brain factors.

Aim: Non-alcoholic steatohepatitis (NASH), or metabolic dysfunction-associated steatohepatitis (MASH), is a severe form of non-alcoholic fatty liver disease (NAFLD) or metabolic dysfunction-associated liver disease (MASLD), that may progress to advanced liver disease. Costs associated with progression are not well characterized. This study sought to quantify costs and healthcare resource utilization (HRU) associated with NASH progression. Methods: Patients were included if diagnosed with NASH (ICD-10: K75.81) in 100% Medicare claims data (2015-2021) who were ≥66 years at index (diagnosis), continuously enrolled in Parts A, B and D for ≥12 months prior to and 6 months following index (unless death) and who had no evidence of other causes of liver disease. Patient-time was categorized into five severity states: non-cirrhotic NASH, compensated cirrhosis (CC), decompensated cirrhosis (DCC), hepatocellular carcinoma (HCC) and liver transplant (LT). Annualized HRU and costs were calculated during the study periods overall and stratified by occurrence and timing of progression. Results: In 14,806 unique patients (n = 12,990 non-cirrhotic NASH; 1899 CC; 997 DCC; 209 HCC; 140 LT), mean age and follow-up were 72.2 and 2.8 years, respectively. Average annualized costs increased from baseline following diagnosis, generally scaling with severity: $16,231 to $27,044; $25,122 to $57,705; $40,613 to $181,036; $36,549 to $165,121 and $35,626 to $108,918 in NASH; CC; DCC; HCC; and LT; respectively. Non-cirrhotic NASH and CC patients with progression had higher follow-up spending (1.6x for NASH; 1.7x for CC) than non-progressors (both p < 0.001), 2.8 and 6.1-times higher odds of an inpatient stay and 2.6 and 3.6-times higher odds to be in the top 20% of spenders, respectively, relative to non-progressors (both p < 0.001). Patients progressing within a year had costs 1.4, 1.6, 1.7 and 2.2-times more than year 2, 3, 4 and 5 progressors' costs, respectively, for non-cirrhotic NASH and 1.3, 1.8, 2.0 and 2.2-times more than year 2, 3, 4 and 5 progressors' costs, respectively, for CC. Conclusion: NASH progression is associated with high costs that increase in more severe disease states. Slower progression is associated with lower costs, suggesting a potential benefit of therapies that may delay or prevent progression.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide and can progress to serious complications, including metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Predisposing risk factors for MASH include obesity, type 2 diabetes, dyslipidemia, and metabolic syndrome. Patients with MASH often experience significant impairments in their health-related quality of life and other patient-reported outcomes (PROs), particularly in physical functioning domains, fatigue, and vitality. Incorporating PROs offers valuable insights into patients' perspectives on their symptoms, treatment efficacy, and overall well-being, thereby guiding more holistic and patient-centered care strategies. This review aims to investigate the utilization of patient-reported outcome measures (PROMs) in the context of MASLD and MASH care, identify which PROMs are employed, and summarize the outcomes reported.

Long-term Western diet-induced non-alcoholic steatohepatitis (NASH) can lead to liver cirrhosis and NASH-associated hepatocellular carcinoma, which are end-stage liver diseases. Meanwhile, NASH is associated with mental burden and worsens as the disease progresses. Atractylodes Macrocephala Koidz (AMK) is one of the main ingredients of Shenling Baizhu San, and the effect of Polysaccharide from AMK ameliorates (PAMK), as an important medicinal ingredient of AMK, on NASH and associated anxiety/depression-like behaviors is still unclear.

This study investigated the protective effect of PAMK on NASH and associated anxiety/depression-like behaviors through a Western diet-induced NASH mice model.

showed that PAMK decreased the concentrations of liver TC, TG, and serum AST and ALT, improving glucose tolerance, and reducing liver steatosis and fibrosis. Moreover, the expression of liver IL-6, IL-1β, TNF-α, IL-18 and MCP-1 could be reduced by PAMK significantly. Additionally, PAMK decreased anxiety/depression-like behaviors and expression of IL-6, IL-1β, TNF-α, and MCP-1 in the hippocampus. 16S rRNA gene sequencing revealed that PAMK diminished the Firmicutes/Bacteroidetes ratio and abundance of Faecalibaculum_rodentium, and increased the abundance of Muribaculaceae. This might be related to gene abundance of Pentose, the glucuronate interconversions pathway and carbohydrate enzymes (GH1, GH4). Serum metabolomics suggested that PC (18:5e/2:0), PC (16:2e/2:0), Lysopc 20:4, PC (16:0/2:0), and LPC 19:0 upregulated significantly after PAMK intervention, together with the enrichment of carbon metabolism and Citrate cycle pathways specially.

PAMK as a potential prebiotic ameliorated NASH and associated anxiety/depression-like behaviors in mice, probably by regulating Faecalibaculum_rodentium, carbohydrate enzymes and lipid metabolites.

We aimed to characterize quality of life (QOL) trajectories among patients with intermediate and advanced hepatocellular carcinoma patients treated with immunotherapy.

Barcelona Clinic Liver Cancer (BCLC) stage B-C HCC patients receiving immunotherapy at Guangxi Medical University Cancer Hospital were included. Trajectories of QOL, assessed using the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) questionnaire, were identified through iterative estimations of group-based trajectory models. Associations with trajectory group membership were analyzed using multivariable multinomial logistic regression.

Three trajectory groups were identified (n=156): excellent (35.3%), poor (43.6%), and deteriorating (21.1%) QOL. The deteriorating trajectory group reported a mean QOL score of 124.79 (95% CI, 116.58-133.00), but then declined significantly at month-2 (estimated QOL score 98.67 [95% CI, 84.33-113.00]), and the lowest mean score is reached at month-6 (estimated QOL score 16.58 [95% CI, 0-46.07]). Factors associated with membership to the deteriorating group included no drinking (odds ratio [OR] vs yes [95% CI], 3.70 [1.28-11.11]), no received radiotherapy (OR vs yes [95% CI], 8.33 [1.41-50.00]), diabetes (OR vs no [95% CI], 6.83 [1.57-29.73]), and extrahepatic metastasis (OR vs no [95% CI], 3.08 [1.07-8.87]). Factors associated with membership to the poor group also included body mass index ≤24.0 kg/m2 (OR vs no [95% CI], 4.49 [1.65-12.22]).

This latent-class analysis identified a high-risk cluster of patients with severe, persistent post-immunotherapy QOL deterioration. Screening relevant patient-level characteristics may inform tailored interventions to mitigate the detrimental impact of immunotherapy and preserve QOL.

Background/Objectives: Body composition (BC) affects the risk of developing metabolic dysfunction-associated steatotic liver disease (MASLD) and hypertension (HTN). Currently, dual-energy X-ray absorptiometry (DEXA) is considered the gold standard for assessing BC, even though it has some limitations, including immobility, ionizing radiation, and patient weight restrictions. The aim of the study was to evaluate the correlations of BC parameters measured by bioelectrical impedance analysis (BIA) with those measured by DEXA in patients with MASLD and HTN. Methods: Overall, 78 patients with MASLD and HTN underwent the following study procedures: compilation of an anamnesis, physical examination of a patient, laboratory tests, abdominal ultrasound, BIA, DEXA, and anthropometric measurements. Results: The agreement between BIA and DEXA in diagnosing reduced skeletal muscle mass (SMM) in patients with MASLD and HTN was moderate (kappa values were 0.440 and 0.404 in males and females, respectively). Significant strong direct correlations were found between fat mass (FM) and body fat percentage measured by BIA with corresponding measurements by DEXA (p < 0.001 for both). The area under the receiver operating characteristic curves (AUC) of SMM to body weight ratios calculated using BIA data were 0.834 and 0.929 for reduced appendicular SMM determined by DEXA in males and females with MASLD and HTN, respectively. Conclusions: In conclusion, BIA is an easy-to-use and widely available tool for assessing SMM and FM in patients with MASLD and HTN, demonstrating reliable agreement with DEXA measurement results and completely free of its limitations.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the liver manifestation of a metabolic syndrome and is highly prevalent in the general population. There has been significant progress in non-invasive tests for MAFLD, from the diagnosis of fatty liver and monitoring of liver fat content in response to intervention, to evaluation of liver fibrosis and its change over time, and from risk stratification of patients within the context of clinical care pathways, to prognostication. Various non-invasive tests have also been developed to assess for fibrotic metabolic dysfunction-associated steatohepatitis, which has emerged as an important diagnostic goal, particularly in the context of clinical trials. Non-invasive tests can be used to diagnose clinically significant portal hypertension so that intervention can be administered to reduce the risk of decompensation. Furthermore, the use of risk stratification algorithms can identify at-risk patients for hepatocellular carcinoma surveillance. Beyond the liver, various tests that evaluate cardiovascular disease risk, assess sarcopenia and measure patient reported outcomes, can be utilized to improve the care of patients with MAFLD. This review provides an up-to-date overview of these non-invasive tests and the limitations of liver biopsy in the management of patients with MAFLD.

Aim: A clinical decision support (CDS) tool for metabolic dysfunction-associated steatohepatitis (MASH) was developed to align health systems with clinical guidelines detailed in the MASH Clinical Care Pathway and improve patients' proactive self-management of their disease. The tool includes a provider-facing web-based application and a mobile application (app) for patients. This protocol outlines a pilot study that will systematically evaluate the implementation of the tool in real-world clinical practice settings. Materials & methods: This implementation research study will use a simultaneous mixed-methods design and is guided by the Consolidated Framework for Implementation Research. The CDS tool for MASH will be piloted for ≥3 months at multiple US-based sites with eligible gastroenterologists and hepatologists (n = 5-10 per site) and their patients (n = 50-100 per site) with MASH or suspected MASH. Each pilot site may choose one or all focus areas within the tool (i.e., risk stratification, screening and referral, or patient care management), based on on-site capabilities. Prior to and at the end of the pilot period, providers and patients will complete quantitative surveys and partake in semi-structured interviews. Outcomes will include understanding the feasibility of implementing the tool in real-world clinical settings, its effectiveness in increasing patient screenings and risk stratification for MASH, its ability to improve provider and patient knowledge of MASH, barriers to adoption of the tool and the tool's capacity to enhance patient engagement and satisfaction with their care. Conclusion: Findings will inform the scalable implementation of the tool to ensure patients at risk for MASH are identified early, referred to specialty care when necessary and managed appropriately. Successful integration of the patient app can contribute to better health outcomes for patients by facilitating their active participation in the management of their condition.

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

The intersection of cardiovascular disease, metabolic disorders and chronic kidney disease represents a complex clinical picture challenging healthcare systems worldwide. Metabolic-dysfunction-associated steatotic liver disease (MASLD) often manifests sequentially or concomitantly with these diseases, and may share underlying mechanisms and risk factors. Growing evidence suggests that new therapies could have benefits across these diseases, but trial sponsors and investigators tend to be reluctant to include patients with comorbidities-particularly liver diseases-in clinical trials. In this Perspective, we call for inclusion of patients with MASLD and measurement of liver outcomes in cardio-kidney-metabolic trials, when data suggest mechanistically plausible benefits and liver and cardiovascular safety. We discuss the implications of this new paradigm for clinical trial design and considerations for regulatory approval. Finally, we outline the challenges to implementing such an approach and provide recommendations for future clinical trial conduct.

Nonalcoholic steatohepatitis (NASH)/metabolic dysfunction-associated steatohepatitis (MASH) is an advanced form of liver disease that can lead to significant morbidity and mortality primarily due to hepatic complications including fibrosis, cirrhosis, hepatocellular carcinoma, and liver failure, as well as cardiovascular disease. As the development of NASH/MASH is closely linked to cardiometabolic risk factors such as obesity and type 2 diabetes mellitus, its prevalence is increasing along with the prevalence of those conditions. Identifying at-risk patients or those early in the disease process is essential to optimizing care and may prevent future complications. Current treatment options include disease-modifying interventions, off-label use of US Food and Drug Administration (FDA)-approved medications for comorbid conditions, and resmetirom, the recently first-ever FDA-approved medication specifically for use in NASH/MASH. There is also considerable continued activity in related drug development research with several other potential emerging treatments. With the increasing prevalence of NASH/MASH and emerging treatments, it is important for managed care organizations (MCOs) to be prepared to assist in patient care and implement equitable treatment management. Understanding patient perspectives and their experience with NASH/MASH provides insights for MCOs such as the need for education of both health care providers and patients to encourage early diagnosis and for enhancing access to individualized care including resources and support. Additionally, MCOs can consider potential management strategies for new and emerging treatments.

With the implementation of the 11th edition of the International Classification of Diseases (ICD-11) and the publication of the metabolic dysfunction-associated fatty liver disease (MAFLD) nomenclature in 2020, it is important to establish consensus for the coding of MAFLD in ICD-11. This will inform subsequent revisions of ICD-11.

Using the Qualtrics XM and WJX platforms, questionnaires were sent online to MAFLD-ICD-11 coding collaborators, authors of papers, and relevant association members.

A total of 890 international experts in various fields from 61 countries responded to the survey. We also achieved full coverage of provincial-level administrative regions in China. 77.1% of respondents agreed that MAFLD should be represented in ICD-11 by updating NAFLD, with no significant regional differences (77.3% in Asia and 76.6% in non-Asia, p = 0.819). Over 80% of respondents agreed or somewhat agreed with the need to assign specific codes for progressive stages of MAFLD (i.e. steatohepatitis) (92.2%), MAFLD combined with comorbidities (84.1%), or MAFLD subtypes (i.e., lean, overweight/obese, and diabetic) (86.1%).

This global survey by a collaborative panel of clinical, coding, health management and policy experts, indicates agreement that MAFLD should be coded in ICD-11. The data serves as a foundation for corresponding adjustments in the ICD-11 revision.

Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of liver disease. Dynamic changes in MRI proton-density-fat fraction (PDFF) are associated with MASH resolution. We aimed to determine the relative efficacy of therapeutic agents for reducing hepatic fat, assessed by MRI-PDFF.

In this systematic review and network meta-analysis, we searched MEDLINE and Embase from inception until December 26, 2023, for published randomized controlled trials comparing pharmacological interventions in patients with MASH that assessed changes in MRI-PDFF. The primary outcome was the absolute change in MRI-PDFF. The secondary outcome was a ≥30% decline in MRI-PDFF. A surface under-the-curve cumulative ranking probabilities (SUCRA) analysis was performed. Of 1550 records, a total of 39 randomized controlled trials (3311 participants) met the inclusion criteria. For MRI-PDFF decline at 24 weeks, aldafermin (SUCRA: 83.65), pegozafermin (SUCRA: 83.46), and pioglitazone (SUCRA: 71.67) were ranked the most effective interventions. At 24 weeks, efinopegdutide (SUCRA: 67.02), semaglutide + firsocostat (SUCRA: 62.43), and pegbelfermin (SUCRA: 61.68) were ranked the most effective interventions for achieving a ≥30% decline in MRI-PDFF.

This study provides an updated, relative rank-order efficacy of therapies for MASH in reducing hepatic fat. These data may help inform the design and sample size calculation of future clinical trials and assist in the selection of combination therapy.

Steatotic liver disease (SLD) is a worldwide public health problem, causing considerable morbidity and mortality. Patients with SLD are at increased risk for major adverse cardiovascular (CV) events, type 2 diabetes mellitus and chronic kidney disease. Conversely, patients with cardiometabolic conditions have a high prevalence of SLD. In addition to epidemiological evidence linking many of these conditions, there is evidence of shared pathophysiological processes. In December 2022, a unique multi-stakeholder, multi-specialty meeting, called MOSAIC (Metabolic multi Organ Science Accelerating Innovation in Clinical Trials) was convened to foster collaboration across metabolic, hepatology, nephrology and CV disorders. One of the goals of the meeting was to consider approaches to drug development that would speed regulatory approval of treatments for multiple disorders by combining liver and cardiorenal endpoints within a single study. Non-invasive tests, including biomarkers and imaging, are needed in hepatic and cardiorenal trials. They can be used as trial endpoints, to enrich trial populations, to diagnose and risk stratify patients and to assess treatment efficacy and safety. Although they are used in proof of concept and phase 2 trials, they are often not acceptable for regulatory approval of therapies. The challenge is defining the optimal combination of biomarkers, imaging and morbidity/mortality outcomes and ensuring that they are included in future trials while minimizing the burden on patients, trialists and trial sponsors. This paper provides an overview of some of the wide array of CV, liver and kidney measurements that were discussed at the MOSAIC meeting.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a predominant chronic liver condition globally and is strongly associated with obesity, diabetes mellitus, and dyslipidemia. Essential phospholipids (EPL) are recommended as supportive treatment for managing liver conditions, including MASLD or metabolic dysfunction-associated steatohepatitis, cirrhosis, and viral hepatitis. While efficacy of EPL as an adjunctive therapy in MASLD treatment has been established earlier, certain aspects of its usage such as the impact of standard-of-care parameters, effect of EPL on quality of life (QoL) and change in symptoms evaluation in patients with MASLD remain unexplored. The proposed trial aims to assess the efficacy and safety of EPL and the subsequent QoL of patients with MASLD associated with type 2 diabetes mellitus (T2DM) and/or hyperlipidemia and/or obesity.

This is a multicenter, multinational, double-blind, randomized, two-arm, placebo-controlled, parallel-group, phase IV clinical trial. The trial is being conducted in approximately 190 patients who are randomized on a 1:1 basis either to the EPL arm (Essentiale® 1800 mg/day orally + standard of care) or placebo arm (placebo + standard of care). The primary outcome is to assess the efficacy of EPL on hepatic steatosis, as measured by transient elastography, from baseline to 6 months. The secondary outcomes include change in QoL parameters, as measured by the Chronic Liver Disease Questionnaire-metabolic dysfunction-associated steatotic liver disease/ metabolic dysfunction-associated steatohepatitis and change in symptom evaluation (using the Global Overall Symptom scale) from baseline to 6 months for symptoms, including asthenia, feeling depressed, abdominal pain/discomfort, or fatigue.

The current protocol design will allow to comprehensively explore the efficacy of EPL added to the standard of care on hepatic steatosis and QoL and its safety in patients with MASLD associated with T2DM and/or hyperlipidemia and/or obesity by assessing various outcome measures.

European Union Clinical Trials Register, EudraCT, 2021-006069-39. Registered on March 13, 2022.

The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) is continuously rising, evolving into a global health challenge. Concurrently, cases of hepatocellular carcinoma (HCC) associated with MASLD are also on the increase. Although traditional risk factors such as age, gender, and metabolic factors play significant roles in the development of HCC, it cannot be overlooked that MASLD, triggered by changes in modern lifestyle and dietary habits, may also exacerbate the risk of HCC, and this phenomenon is common even among non-obese individuals. Regrettably, MASLD often fails to receive timely diagnosis, resulting in a limited number of patients receiving HCC surveillance. Moreover, there is currently a lack of clear definition for the target population for surveillance beyond patients with cirrhosis. Consequently, MASLD-related HCC is often detected at a late stage, precluding the optimal timing for curative treatment. However, our understanding of the pathogenesis and progression of HCC remains limited. Therefore, this paper reviews relevant literature from recent years, delving into multiple dimensions such as pathogenesis, surveillance and diagnosis, prevention, and treatment, aiming to provide new ideas and directions for the prevention and treatment of MASLD-related HCC.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are a growing health burden across a significant portion of the global patient population. However, these conditions seem to have disparate rates and outcomes between different ethnic populations. The combination of MASLD/MASH and type 2 diabetes increases the risk of hepatocellular carcinoma (HCC), and Hispanic patients experience the greatest burden, particularly those in South Texas.

To compare outcomes between Hispanic and non-Hispanic patients in the United States, while further focusing on the Hispanic population within Southeast Texas to determine whether the documented disparity in outcomes is a function of geographical circumstance or if there is a more widespread reason that all clinicians must account for in prognostic consideration.

This cohort analysis was conducted with data obtained from TriNetX, LLC ("TriNetX"), a global federated health research network that provides access to deidentified medical records from healthcare organizations worldwide. Two cohort networks were used: University of Texas Medical Branch (UTMB) hospital and the United States national database collective to determine whether disparities were related to geographic regions, like Southeast Texas.

This study findings revealed Hispanics/Latinos have a statistically significant higher occurrence of HCC, type 2 diabetes mellitus, and liver fibrosis/cirrhosis in both the United States and the UTMB Hispanic/Latino groups. All-cause mortality in Hispanics/Latinos was lower within the United States group and not statistically elevated in the UTMB cohort.

This would appear to support that Hispanic patients in Southeast Texas are not uniquely affected compared to the national Hispanic population.

It is unclear what biopsychosocial factors influence the impact of NAFLD on health-related quality of life (HRQoL), and if these factors are equally important predictors between different nationalities.

HRQoL (CLDQ) was measured in both Southern European (Spain, n = 513) and Northern European (United Kingdom -UK-, n = 224) cohorts of patients with NAFLD in this cross-sectional study. For each cohort, participant data were recorded on histological grade of steatohepatitis, stage of fibrosis and biopsychosocial variables. Regression analysis was used to explore which of these variables predicted HRQoL. Moderated mediation models were conducted using SPSS PROCESS v3.5 macro.

Participants with severe fibrosis reported more fatigue, systemic symptoms and worry, and lower HRQoL than those with none/mild fibrosis, regardless of place of origin. In addition, body mass index (BMI) and gender were found to be significant predictors of HRQoL in both Spanish and UK participants. Female gender was associated with worse emotional function, higher BMI and more fatigue, which predicted lower participants' HRQoL. UK participants showed more systemic symptoms and worry than Spanish participants, regardless of liver severity. The negative effects of gender on HRQoL through emotional function, BMI and fatigue were reported to a greater degree in UK than in Spanish participants.

UK participants showed a greater impairment in HRQoL as compared to Spanish participants. Higher fibrosis stage predicted lower HRQoL, mainly in the Spanish cohort. Factors such as female gender or higher BMI contributed to the impact on HRQoL in both cohorts of patients and should be considered in future multinational intervention studies in NAFLD.

Farnesoid X receptor (FXR) plays a pivotal role in the regulation of bile acid homeostasis and is involved in the pathogenesis of nonalcoholic steatohepatitis (NASH). Although FXR agonists effectively alleviate pathological features of NASH, adverse effects such as disturbance of cholesterol homeostasis and occurrence of pruritus remain to be addressed. Here, we identified a novel FXR agonist, ID119031166 (ID166), and explored the pharmacological benefits of ID166 in the treatment of NASH. ID166, a potent and selective non-bile acid FXR agonist, exhibits preferential distribution in the intestine and shows no agonist activity against potential itch receptors including Mas-related G protein-coupled receptor X4 (MRGPRX4). Interestingly, ID166 significantly attenuated total nonalcoholic fatty liver disease (NAFLD) activity and liver fibrosis in a free choice diet-induced NASH hamster model. In addition, ID166 drastically modulated the relative abundance of five gut microbes and reduced the increase in plasma total bile acid levels to normal levels in NASH hamsters. Moreover, long-term treatment with ID166 significantly improved key histological features of NASH and liver fibrosis in a diet-induced NASH mouse model. In the NASH mouse livers, RNA-seq analysis revealed that ID166 reduced the gene expression changes associated with both NASH and liver fibrosis. Notably, ID166 exhibited no substantial effects on scratching behavior and serum IL-31 levels in mice. Our findings suggest that ID166, a novel FXR agonist with improved pharmacological properties, provides a preclinical basis to optimize clinical benefits for NASH drug development.

There has been an exponential increase in the global prevalence of fatty liver disease in recent years in association with the obesity pandemic worldwide. 'Metabolic dysfunction-associated fatty liver disease', the new terminology adopted by an international panel of experts in 2020 to largely replace the old term 'non-alcoholic fatty liver disease', has now been accepted by most hepatologists and diabetologists across the globe. The term metabolic dysfunction-associated fatty liver disease was created to better reflect the metabolicand liver-specific manifestations and complications of fatty liver disease. It is important to disseminate our current understanding of this enigmatic disease among the global scientific fraternity. Recent publications, including articles from the latest issue of Endocrinology & Metabolism Clinics of North America, are attempting to fill this knowledge gap.

The utility of the EuroQol Group 5 Dimension (EQ-5D) measuring health-related quality of life (HRQoL) has been verified; however, knowledge gaps remain concerning predictive performance in cirrhosis. We aimed to identify the optimal threshold for risk stratification and the pronounced domain in the EQ-5D linked to inferior outcomes.

The X-tile project was used to obtain a threshold, considering the composite outcome of 1-year all-cause mortality or readmission. A restricted cubic spline (RCS) was performed to test the non-linear relationship between the EQ-5D utility value and the primary outcome. Six multivariate Cox regression models incorporating EQ-5D utility value and each of the five domains were constructed.

Totally, 420 patients with cirrhosis were recruited.

The median utility value of the study population was 0.77 and 59.8% reported impairment in minimal one EQ-5D domain. RCS indicated a linear relationship between the utility value and composite inferior outcome. X-tile pinpointed a utility value of 0.59 stratifying populations into high- and low-risk groups based on the outcome. Inpatients with cirrhosis and deteriorated HRQoL (utility value ≤0.59) were at higher risk of death or readmission (adjusted HR: 2.18, P < 0.001). Furthermore, mobility and usual activities were the most pronounced domains associated with composite inferior outcome.

A utility value ≤0.59 can identify cirrhotic inpatients exhibiting compromised HRQoL and mortality/readmission risk. It is tempting to reverse the decreased HRQoL by applying longitudinal measurements and keeping surveillance on utility value, while interventions appear to mainly focus on improving mobility and usual activities.

The prevalence of nonalcoholic fatty liver disease (NAFLD) in the United States is 38%, having increased by 50% within the past 3 decades. The estimated NAFLD prevalence among people with type 2 diabetes is 55-70%. The presence of type 2 diabetes is associated with a higher likelihood of progression of NAFLD to fibrosis development, liver transplant, and death. Cardiovascular disease is the main cause of mortality among people with NAFLD, and the risk of death is significantly higher in people with both NAFLD and type 2 diabetes. NAFLD carries high patient and economic burdens but low awareness among both the general public and health care providers. This article reviews the epidemiology of NAFLD and discusses the need for appropriate risk stratification, referral for specialty care, management of cardiometabolic risk factors, and treatment of the disease. The authors present a call to action to raise awareness of NAFLD and address its increasing burden in a systematic and efficient manner.

Nonalcoholic fatty liver disease (NAFLD) is the most common hepatic disease affecting almost 30% of the world population. Approximately 25% of people with NAFLD develop nonalcoholic steatohepatitis (NASH), the fulminant version of the disease. Diabetes mellitus is present in 22.5% of people with NAFLD and 44.60% of individuals with NASH. This review was undertaken to examine the current contribution of glucagon-like peptide 1 (GLP-1) receptor agonists to the pharmacotherapy of diabetic nonalcoholic steatohepatitis.

The author analyzed the current status of GLP-1 receptor agonists for pharmacotherapy of diabetic NASH. Research data and literature reports were taken from the database and or websites of Diabetes UK, American Diabetes Association, ClinicalTrials.gov, PubMed, and Scopus. The keywords utilized included type 2 diabetes, GLP-1, NASH, NAFLD, and clinical trials.

Since diabetic NASH is associated with obesity, diabetes mellitus, oxidative stress and inflammation, drugs capable of mitigating all of these conditions simultaneously, are most ideal for the treatment of diabetic NASH. These drugs include (in order of relevance), GLP-1 receptor agonists, GLP-1 and GIP dual receptor agonists, sodium-glucose co-transporter-2 (SGLT2) inhibitors, and pioglitazone. The future, FDA-approved drug for diabetic NASH treatment will likely be GLP-1 agonist, which could be used as monotherapy or in combination with other drugs.

Patients with metabolic dysfunction-associated steatotic liver disease (MASLD) are often comorbid and stigmatized. This can negatively affect quality of life (QOL). Other studies have primarily used the Chronic Liver Disease Questionnaire (CLDQ), which focuses on liver-related symptoms, to characterize QOL, but most MASLD patients have only mild liver disease, and CLDQ might overlook QOL issues pertaining to them. We aimed to determine the impact of metabolic dysfunction-associated steatohepatitis (MASH) on QOL in obese patients using a 136-item generic QOL questionnaire.

We included participants with BMI ≥ 35 kg/m2 who all fully answered the sickness impact profile (SIP, range 0-100, normal = 3.4, 100 = worst) and had a liver biopsy to diagnose MASLD. Sociodemographics, comorbidity and biometric data were obtained from all participants.

Of 176 (mean age 45.9 years, 70% female, 12.6 years of education), 132 had no-MASH and 44 MASH. On stepwise multivariable regression analysis, divorce (p = .011), unemployment (p < .003) and hepatic steatosis (p = .01) were associated with poor overall QOL. No other somatic comorbidity was associated. MASH patients more frequently than no-MASH reported physical discomfort (48% vs. 30%, p = .04), inability to do daily activities (29% vs. 54%, p = .006) and attention problems (32% vs. 57%, p = .003).

MASLD severity was the only somatic determinant of QOL in patients with obesity in this cohort, and a large fraction reported debilitating symptoms. Patients and caregivers should consider the limitations this poses when planning interventions.

To describe the clinical profile of nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH) patients in a Texas integrated delivery network (IDN) and elucidate the local relationship between patient factors and the risk of advanced fibrosis.

This observational, retrospective, cross-sectional study utilized existing data from the electronic health record at a large Texas IDN. Data was collected during the study period from 1 January 2019, to 1 March 2023. Patient characteristics, comorbidities, labs, and medication orders were collected from the most recent encounter in which a Fibrosis-4 (FIB-4) score could be calculated. Chi square tests and analysis of variance (ANOVA) tests were conducted to evaluate differences among the three fibrosis risk categories. Ordinal logistic regression was utilized to assess associations between select variables and a higher risk of advanced fibrosis.

A total of 56,253 patients were included in the study. 34,839 (61.9%) were Low-Risk 15,578 (27.7%) were Intermediate-Risk, and 5,836 (10.4%) were High-Risk of advanced fibrosis. Results showed that up to 70.4% of patients within a risk group were obese. Only 49.5% of patients in the High-Risk group had at least one gastroenterologist or hepatologist visit. Males, Medicare patients, former smokers, and those with hypertension, type 2 diabetes, and chronic kidney disease were associated with a higher risk of advanced fibrosis.

This study highlights the need for early screening and proactive management of metabolic risk factors for patients with NAFLD/NASH. The findings indicate a notable prevalence of obesity in the study population, a need for specialist referral for those at High-Risk of advanced fibrosis, and the importance of routine labs to evaluate metabolic factors. Primary care providers may be ideal providers to target these interventions and address this care need.