Metabolic dysfunction-associated steatotic liver disease: heterogeneous pathomechanisms and effectiveness of metabolism-based treatment.

The global epidemic of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing worldwide. People with MASLD can progress to cirrhosis and hepatocellular carcinoma and are at increased risk of developing type 2 diabetes, cardiovascular disease, chronic kidney disease, and extrahepatic cancers. Most people with MASLD die from cardiac-related causes.

Environmental toxicants modulate disease severity in pediatric metabolic dysfunction-associated steatohepatitis.

Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is common in children. We hypothesized environmental toxins could drive progression to metabolic dysfunction-associated steatohepatitis (MASH), and assayed serum toxins and metabolites in children with histologically characterized MASLD/MASH.

Methods: Environmental chemicals, common in household items, perfluoroalkyl substances (PFAS), polybrominated flame retardants (polybrominated diphenyl ethers [PBDEs]), and metabolic profiles were assayed in children enrolled in the multicenter NASH Clinical Research Network Pediatric Database 2.

Fibrosis, biomarkers and liver biopsy in AAT deficiency and relation to liver Z protein polymer accumulation.

Background And Aims: The course of adults with ZZ alpha-1-antitrypsin deficiency (AATD) liver disease is unpredictable. The utility of markers, including liver biopsy, is undefined.

Methods: A prospective cohort, including protocol liver biopsies, was enrolled to address these questions.

Liver stiffness progression in biopsy-proven metabolic dysfunction-associated steatotic disease among people with diabetes versus people without diabetes: A prospective multicenter study.

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

Approach And Results: This study included 1231 adult participants (62% female) with biopsy-proven metabolic dysfunction-associated steatotic liver disease who had VCTEs at least 1 year apart.

High Concordance Between Nonalcoholic Fatty Liver Disease and Metabolic Dysfunction-Associated Steatotic Liver Disease in the TARGET-NASH Real-World Cohort.

Introduction: This study investigates the applicability of the new metabolic dysfunction-associated steatotic liver disease (MASLD) nomenclature to the real-world TARGET-NASH US adult cohort.

Methods: The new MASLD/metabolic steatohepatitis nomenclature was applied to patients enrolled with pragmatic diagnoses of nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH), and NASH cirrhosis and concordance were determined between the definitions.

Results: Approximately 99% of TARGET-NASH participants met the new MASLD diagnostic criteria.

Metabolic dysfunction-associated steatotic liver disease: Update and impact of new nomenclature on the American Association for the Study of Liver Diseases practice guidance on nonalcoholic fatty liver disease.

This commentary discusses how clinicians and various stakeholders can utilize the recently published American Association for the Study of Liver Diseases nonalcoholic fatty liver disease (AASLD NAFLD) Practice Guidance in light of the change in the nomenclature to steatotic liver disease and its subcategories. The new terminologies explained in this commentary make it easier for the readers to interchangeably use metabolic dysfunction-associated steatotic liver disease (MASLD) in place of NAFLD and metabolic-dysfunction associated steatohepatitis (MASH) instead of nonalcoholic steatohepatitis (NASH), respectively, as they read the NAFLD Practice Guidance. The guidance document is relevant and can be utilized for the diagnosis, risk stratification, and management of patients with MASLD.

Age, BMI, and Type 2 Diabetes Modify the Relationship Between PNPLA3 and Advanced Fibrosis in Children and Adults With NAFLD.

Background & Aims: PNPLA3 G-allele is an important determinant of disease severity in nonalcoholic fatty liver disease (NAFLD). Here, we investigated the effect of age, body mass index (BMI), and type 2 diabetes mellitus (T2DM) on the relationship between PNPLA3 G-allele and advanced fibrosis in adults and children with histologically characterized NAFLD.

Methods: A total of 1047 children and 2057 adults were included.

Inhibition of integrin binding to ligand arg-gly-asp motif induces AKT-mediated cellular senescence in hepatic stellate cells.

Background & Aims: Hepatic stellate cells (HSCs) play an essential role in liver fibrogenesis. The induction of cellular senescence has been reported to inhibit HSC activation. Previously, we demonstrated that CWHM12, a small molecule arginine-glycine-aspartic acid (RGD) peptidomimetic compound, inhibits HSC activation.

Diagnostic performance of circulating biomarkers for non-alcoholic steatohepatitis.

There are no approved diagnostic biomarkers for at-risk non-alcoholic steatohepatitis (NASH), defined by the presence of NASH, high histological activity and fibrosis stage ≥2, which is associated with higher incidence of liver-related events and mortality. FNIH-NIMBLE is a multi-stakeholder project to support regulatory approval of NASH-related biomarkers. The diagnostic performance of five blood-based panels was evaluated in an observational (NASH CRN DB2) cohort (n = 1,073) with full spectrum of non-alcoholic fatty liver disease (NAFLD).

Ube4A maintains metabolic homeostasis and facilitates insulin signaling in vivo.

Objective: Defining the regulators of cell metabolism and signaling is essential to design new therapeutic strategies in obesity and NAFLD/NASH. E3 ubiquitin ligases control diverse cellular functions by ubiquitination-mediated regulation of protein targets, and thus their functional aberration is associated with many diseases. The E3 ligase Ube4A has been implicated in human obesity, inflammation, and cancer.

Enhancing Hepatic MBOAT7 Expression in Mice With Nonalcoholic Steatohepatitis.

Background And Aims: Polymorphisms near the membrane bound O-acyltransferase domain containing 7 (MBOAT7) genes are associated with worsened nonalcoholic fatty liver (NASH), and nonalcoholic fatty liver disease (NAFLD)/NASH may decrease MBOAT7 expression independent of these polymorphisms. We hypothesized that enhancing MBOAT7 function would improve NASH.

Methods: Genomic and lipidomic databases were mined for MBOAT7 expression and hepatic phosphatidylinositol (PI) abundance in human NAFLD/NASH.

Pegbelfermin in Patients With Nonalcoholic Steatohepatitis and Compensated Cirrhosis (FALCON 2): A Randomized Phase 2b Study.

Background & Aims: Pegbelfermin is a polyethylene glycol-conjugated analog of human fibroblast growth factor 21, a nonmitogenic hormone that regulates energy metabolism. This phase 2b study evaluated 48-week pegbelfermin treatment in patients with nonalcoholic steatohepatitis (NASH) with compensated cirrhosis.

Methods: FALCON 2 (NCT03486912) was a randomized (1:1:1:1), double-blind, placebo-controlled study.

Pegbelfermin in Patients With Nonalcoholic Steatohepatitis and Stage 3 Fibrosis (FALCON 1): A Randomized Phase 2b Study.

Background & Aims: Pegbelfermin is a polyethlene glycol-conjugated analog of human fibroblast growth factor 21, a nonmitogenic hormone that regulates energy metabolism. This phase 2b study evaluated 48-week pegbelfermin treatment in patients with nonalcoholic steatohepatitis (NASH) and stage 3 (bridging) fibrosis.

Methods: The FALCON 1 study (NCT03486899) was a multicenter, randomized (1:1:1:1), double-blind, placebo-controlled study.

Cenicriviroc Lacked Efficacy to Treat Liver Fibrosis in Nonalcoholic Steatohepatitis: AURORA Phase III Randomized Study.

Background And Aims: Cenicriviroc (CVC) is a novel, orally administered, chemokine receptor type 2 and 5 antagonist that showed antifibrotic potential in preclinical and phase IIb studies of nonalcoholic steatohepatitis (NASH). Herein, we report efficacy and safety results from the phase III study.

Methods: The AURORA (A Study for the Efficacy and Safety of CVC for the Treatment of Liver Fibrosis in Adults With NASH) study was a phase III, randomized, double-blind, placebo-controlled, 2-part study of patients with NASH and stage 2/3 liver fibrosis.

The nonalcoholic steatohepatitis extended hepatocyte ballooning score: histologic classification and clinical significance.

Background And Aims: The NAFLD activity score was developed to measure histologic changes in NAFLD during therapeutic trials. Hepatocyte ballooning (HB) is the most specific feature in steatohepatitis diagnosis, yet the impact of variations in HB has not been incorporated.

Approach And Results: Liver biopsies from patients enrolled in the NASH Clinical Research Network with an initial diagnosis of NASH or NAFL (n=1688) were evaluated to distinguish classic hepatocyte ballooning (cHB) from smaller, nonclassic hepatocyte ballooning (nHB), and also to designate severe ballooning and assign an extended hepatocyte ballooning (eB) score [0 points, no ballooning (NB); 1 point, few or many nHB; 2 points, few cHB; 3 points, many cHB; 4 points, severe cHB] to the biopsy assessment.

The Nimble Stage 1 Study Validates Diagnostic Circulating Biomarkers for Nonalcoholic Steatohepatitis.

Background There are no approved noninvasive tests (NIT) for the diagnosis of nonalcoholic steatohepatitis (NASH) and its histological phenotypes. Methods The FNIH-NIMBLE consortium tested 5 serum-based NIT panels for the following intended uses: NIS4: At-risk NASH, a composite of NASH with NAFLD activity score (NAS) ≥ 4 and fibrosis stage ≥ 2, OWLiver: NASH and NAS ≥ 4, enhanced liver fibrosis (ELF), PROC3 and Fibrometer VCTE: fibrosis stages ≥ 2, ≥ 3 or 4. Aliquots from a single blood sample obtained within 90 days of histological confirmation of NAFLD were tested.

Defining the serum proteomic signature of hepatic steatosis, inflammation, ballooning and fibrosis in non-alcoholic fatty liver disease.

Background & Aims: Despite recent progress, non-invasive tests for the diagnostic assessment and monitoring of non-alcoholic fatty liver disease (NAFLD) remain an unmet need. Herein, we aimed to identify diagnostic signatures of the key histological features of NAFLD.

Methods: Using modified-aptamer proteomics, we assayed 5,220 proteins in each of 2,852 single serum samples from 636 individuals with histologically confirmed NAFLD.

A phase I/II study of ARO-HSD, an RNA interference therapeutic, for the treatment of non-alcoholic steatohepatitis.

Background & Aims: Loss-of-function HSD17β13 mutations protect against the development of chronic liver disease. HSD17β13 inhibition represents a potential approach to treat liver diseases, such as non-alcoholic steatohepatitis (NASH). ARO-HSD is an RNA interference (RNAi) therapeutic designed to selectively reduce expression of HSD17β13 mRNA in hepatocytes.