Hepatic glucose production rises with the histological severity of metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) are associated with a high prevalence of type 2 diabetes (T2D). Individuals with MASLD exhibit insulin resistance (IR) and hyperglycemia, but it is unclear whether hepatic glucose production (HGP) is increased with MASLD severity. We evaluated HGP in a cohort of histologically characterized individuals with MASL/MASH using stable isotope infusion (6,6-H-glucose, U-H-glycerol) and liver-specific genome-scale metabolic models (GEMs).

Variance Between Clinical Guidance and Real-world Management of Metabolic Dysfunction-associated Steatotic Liver Disease in the United States.

Clinical practice guidelines can facilitate diagnosis and management of patients with metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction associated steatohepatitis (MASH), although their implementation to date has been suboptimal. Using recently published 2023 American Association for the Study of Liver Diseases (AASLD) practice guidance-based recommendations as a reference, we assessed current real-world management of patients with MASH to identify gaps in clinical practice. We extracted data from the Adelphi Real World MASH Disease Specific Programme, a cross-sectional survey with retrospective data capture (from 85 hepatologists, gastroenterologists, and endocrinologists [Supplementary Table 1] and 633 patients [Supplementary Table 2] in the United States between January and June 2022).

Needs assessment for creation of a platform trial network in metabolic-dysfunction associated steatohepatitis.

Background: The EU Patient-cEntric clinicAl tRial pLatforms (EU-PEARL) project (IMI2-853966) aimed to develop tools to establish integrated research platforms (IRP) for conducting adaptive-design trials in various diseases, including metabolic-dysfunction associated steatohepatitis (MASH). One essential component of a successful MASH IRP is a robust and reliable Clinical Research Network (CRN). Herein, we outline the required elements and anticipated steps to set-up such a CRN.

An unbiased ranking of murine dietary models based on their proximity to human metabolic dysfunction-associated steatotic liver disease (MASLD).

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease, encompasses steatosis and metabolic dysfunction-associated steatohepatitis (MASH), leading to cirrhosis and hepatocellular carcinoma. Preclinical MASLD research is mainly performed in rodents; however, the model that best recapitulates human disease is yet to be defined. We conducted a wide-ranging retrospective review (metabolic phenotype, liver histopathology, transcriptome benchmarked against humans) of murine models (mostly male) and ranked them using an unbiased MASLD 'human proximity score' to define their metabolic relevance and ability to induce MASH-fibrosis.

How effective are experienced hepatologists at staging fibrosis using non-invasive fibrosis tests in patients with metabolic dysfunction-associated steatotic liver disease?

Background: Sequential use of non-invasive fibrosis tests (NITs) to identify patients with advanced hepatic fibrosis is recommended. However, it remains unclear how reliable clinicians are staging liver fibrosis using combinations of NITs.

Aim: Our aim was to assess concordance between NIT-based 'clinician fibrosis assessment (CFA)' and histology in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and compare this with established algorithmic approaches.

A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis.

Background: Dual agonism of glucagon receptor and glucagon-like peptide-1 (GLP-1) receptor may be more effective than GLP-1 receptor agonism alone for treating metabolic dysfunction-associated steatohepatitis (MASH). The efficacy and safety of survodutide (a dual agonist of glucagon receptor and GLP-1 receptor) in persons with MASH and liver fibrosis are unclear.

Methods: In this 48-week, phase 2 trial, we randomly assigned adults with biopsy-confirmed MASH and fibrosis stage F1 through F3 in a 1:1:1:1 ratio to receive once-weekly subcutaneous injections of survodutide at a dose of 2.

Pharmacogene expression during progression of metabolic dysfunction-associated steatotic liver disease: Studies on mRNA and protein levels and their relevance to drug treatment.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is common worldwide. Genes and proteins contributing to drug disposition may show altered expression as MASLD progresses. To assess this further, we undertook transcriptomic and proteomic analysis of 137 pharmacogenes in liver biopsies from a large MASLD cohort.

New and emerging treatments for metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is a leading etiology of chronic liver disease worldwide, with increasing incidence and prevalence in the setting of the obesity epidemic. MASH is also a leading indication for liver transplantation, given its associated risk of progression to end-stage liver disease. A key challenge in managing MASH is the lack of approved pharmacotherapy.

Diagnostic accuracy of non-invasive tests to screen for at-risk MASH-An individual participant data meta-analysis.

Background & Aims: There is a need to reduce the screen failure rate (SFR) in metabolic dysfunction-associated steatohepatitis (MASH) clinical trials (MASH+F2-3; MASH+F4) and identify people with high-risk MASH (MASH+F2-4) in clinical practice. We aimed to evaluate non-invasive tests (NITs) screening approaches for these target conditions.

Methods: This was an individual participant data meta-analysis for the performance of NITs against liver biopsy for MASH+F2-4, MASH+F2-3 and MASH+F4.

Machine learning approaches to enhance diagnosis and staging of patients with MASLD using routinely available clinical information.

Aims: Metabolic dysfunction Associated Steatotic Liver Disease (MASLD) outcomes such as MASH (metabolic dysfunction associated steatohepatitis), fibrosis and cirrhosis are ordinarily determined by resource-intensive and invasive biopsies. We aim to show that routine clinical tests offer sufficient information to predict these endpoints.

Methods: Using the LITMUS Metacohort derived from the European NAFLD Registry, the largest MASLD dataset in Europe, we create three combinations of features which vary in degree of procurement including a 19-variable feature set that are attained through a routine clinical appointment or blood test.

Serum ferritin levels can predict long-term outcomes in patients with metabolic dysfunction-associated steatotic liver disease.

Objective: Hyperferritinaemia is associated with liver fibrosis severity in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), but the longitudinal implications have not been thoroughly investigated. We assessed the role of serum ferritin in predicting long-term outcomes or death.

Design: We evaluated the relationship between baseline serum ferritin and longitudinal events in a multicentre cohort of 1342 patients.

Prognostic utility of Fibrosis-4 Index for risk of subsequent liver and cardiovascular events, and all-cause mortality in individuals with obesity and/or type 2 diabetes: a longitudinal cohort study.

Background: The Fibrosis-4 Index (FIB-4) is used as a non-invasive tool for the presence of advanced liver fibrosis in metabolic dysfunction-associated steatotic liver disease and type 2 diabetes. However, evidence for an association between FIB-4 and risk of mortality and/or liver-related clinical outcomes is limited. The aim of this study was to investigate the association between FIB-4 and subsequent liver events, cardiovascular events, and all-cause mortality in individuals with obesity and/or type 2 diabetes examined in routine general practice.

Utility of pathologist panels for achieving consensus in NASH histologic scoring in clinical trials: Data from a phase 3 study.

Background: Liver histopathologic assessment is the accepted surrogate endpoint in NASH trials; however, the scoring of NASH Clinical Research Network (CRN) histologic parameters is limited by intraobserver and interobserver variability. We designed a consensus panel approach to minimize variability when using this scoring system. We assessed agreement between readers, estimated linear weighted kappas between 2 panels, compared them with published pairwise kappa estimates, and addressed how agreement or disagreement might impact the precision and validity of the surrogate efficacy endpoint in NASH trials.

NIS2+ as a screening tool to optimize patient selection in metabolic dysfunction-associated steatohepatitis clinical trials.

Background & Aims: Strategies to reduce liver biopsy (LB) screen failures through better patient selection are needed for clinical trials. Standard fibrosis biomarkers were not derived to detect "at-risk" metabolic dysfunction-associated steatohepatitis (MASH; MASH with metabolic dysfunction-associated steatotic liver disease score ≥4 and fibrosis stage ≥2). We compared the performance of screening pathways that incorporate NIS2+™, an optimized version of the blood-based NIS4® technology designed to identify at-risk MASH, with those incorporating fibrosis (FIB)-4 within the RESOLVE-IT clinical trial (NCT02704403), aiming for optimized selection of patients for LB.

FibroScan-aspartate aminotransferase (FAST) score for monitoring histological improvement in non-alcoholic steatohepatitis activity during semaglutide treatment: post-hoc analysis of a randomised, double-blind, placebo-controlled, phase 2b trial.

Background: Currently, assessment of candidate pharmacotherapies in patients with non-alcoholic steatohepatitis (NASH) involves invasive liver biopsy. Non-invasive scores, such as the FibroScan-aspartate aminotransferase (FAST) score, are used to identify candidates for therapy, but their ability to assess disease progression or treatment effect is unknown. We aimed to assess the association between FAST score and histological endpoints.