Age-specific protective effects of statins against cirrhosis in patients with chronic liver enzyme elevation associated with metabolic dysfunction: a retrospective cohort study of electronic health records.

Background: The hepatoprotective effects of statins in chronic liver diseases are well-documented; however, variation by age, sex, and formulation remains unclear. The optimal regimen for cirrhosis prevention has yet to be defined. We aimed to address this knowledge gap.

The Liver in Diabetes and Metabolic Syndrome.

A bidirectonal relationship between insulin resistance, diabetes and metabolic dysfunction-associated steatotic liver disease exists. In those with metabolic syndrome, impairments of glucose and lipid metabolism lead to increased liver fat, necroinflammation (steatohepatitis) and subsequent hepatic fibrosis. An integrated perspective and heightened awareness of metabolic dysfunction associated steatotic liver disease is critical to tempering the rising epidemic metabolic dysfunction associated steatohepatiitis, cirrhosis, liver cancer and need for liver transplanation patients with diabetes and metabolic syndrome.

Altered liver sinusoidal endothelial cells in MASLD and their evolution following lanifibranor treatment.

Background & Aims: Data on changes in liver sinusoidal endothelial cells (LSECs) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and their response to treatment are limited. This study aimed at determining (i) features associated with LSEC capillarisation in patients with MASLD; (ii) whether LSEC changes can regress with the pan-peroxisome proliferator-activated receptor (PPAR) agonist lanifibranor; (iii) the role of the different PPAR isotypes on LSEC changes in MASLD.

Methods: We analysed CD34 expression, a marker of LSEC capillarisation, on liver biopsies from patients considered for inclusion in the NATIVE trial at baseline (n = 249), and after 24 weeks of placebo or lanifibranor (n = 173).

Incident heart failure is common and underrecognized in patients with biopsy-proven metabolic dysfunction-associated steatotic liver disease.

Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with heart failure (HF), independent of shared risk factors. Our aim was to describe the incidence of HF in patients with biopsy-proven MASLD.

Methods And Results: We followed patients with biopsy-proven MASLD from the prospective Duke NAFLD Biorepository and Clinical Database from liver biopsy (2007-2013) until death or 5 January 2023.

ACG Clinical Guideline: Malnutrition and Nutritional Recommendations in Liver Disease.

Malnutrition, defined as deficiency, excess, or imbalance of nutrients, is a common complication in patients with liver disease, especially those with cirrhosis. Malnutrition may present as an isolated micronutrient deficiency, such as zinc deficiency, and it commonly presents as frailty and/or sarcopenia in patients with advanced liver disease. Patients with cirrhosis and/or alcohol-associated hepatitis should be assessed for malnutrition because it adversely affects patient outcomes including mortality, as well as waitlist and posttransplant outcomes among liver transplant candidates.

Targeting senescent hepatocytes for treatment of metabolic dysfunction-associated steatotic liver disease and multi-organ dysfunction.

Senescent hepatocytes accumulate in metabolic dysfunction-associated steatotic liver disease (MASLD) and are linked to worse clinical outcomes. However, their heterogeneity and lack of specific markers have made them difficult to target therapeutically. Here, we define a senescent hepatocyte gene signature (SHGS) using in vitro and in vivo models and show that it tracks with MASLD progression/regression across mouse models and large human cohorts.

ALADDIN: A Machine Learning Approach to Enhance the Prediction of Significant Fibrosis or Higher in Metabolic Dysfunction-Associated Steatotic Liver Disease.

Introduction: The recent US Food and Drug Administration approval of resmetirom for treating metabolic dysfunction-associated steatohepatitis in patients necessitates patient selection for significant fibrosis or higher (≥F2). No existing vibration-controlled transient elastography (VCTE) algorithm targets ≥F2.

Methods: The mAchine Learning ADvanceD fibrosis and rIsk metabolic dysfunction-associated steatohepatitis Novel predictor (ALADDIN) study addressed this gap by introducing a machine-learning-based web calculator that estimates the likelihood of significant fibrosis using routine laboratory parameters with and without VCTE.

Biomarkers of Histological Response in Lanifibranor-treated Patients With Metabolic Dysfunction-associated Steatohepatitis.

Background & Aims: Lanifibranor, a pan-peroxisome proliferator-activated receptor agonist, has demonstrated therapeutic efficacy on metabolic dysfunction-associated steatohepatitis (MASH) resolution and fibrosis improvement in the Phase IIb NATIVE study. The histologic endpoints of MASH resolution and fibrosis improvement (E1), MASH resolution without worsening of fibrosis (E2), and fibrosis improvement without worsening of MASH (E3) were investigated with the aim of identifying biological signatures of E1, E2, and E3 responders based on serum biomarkers in patients treated with lanifibranor.

Methods: NATIVE evaluated lanifibranor 800 and 1200 mg daily vs placebo in patients with non-cirrhotic MASH treated over 24 weeks.

Impact of Weight Loss on Metabolic Dysfunction Associated Steatohepatitis and Hepatic Fibrosis.

Purpose Of Review: This review highlights the impact of weight loss on metabolic dysfunction associated steatotic liver disease (MASLD), formally known as nonalcoholic fatty liver disease (NAFLD), and its progressive form of metabolic dysfunction associated steatohepatitis (MASH), formally known as nonalcoholic steatohepatitis (NASH). The effects of weight loss, as achieved through lifestyle modification, pharmacotherapy, bariatric surgery or endobariatric procedures on MASLD/MASH and hepatic fibrosis are discussed.

Recent Findings: Although foundational in the treatment of MASLD/MASH, weight loss through life-style modification is challenging for most patients to achieve and sustain long-term.

Osteopontin Promotes Cholangiocyte Secretion of Chemokines to Support Macrophage Recruitment and Fibrosis in MASH.

Background And Aims: Osteopontin (OPN) promotes the ductular reaction and is a major driver of chronic liver disease (CLD) progression. Although CLD is characterised by the accumulation of inflammatory cells including macrophages around the peri-portal regions, the influence of OPN on recruitment is unclear. We investigated the role of OPN in cholangiocyte chemokine production and macrophage recruitment by combining in vivo, in vitro, and in silico approaches.

An Infiltrative Case of Angiosarcoma Causing Portal Hypertension.

Hepatic angiosarcoma is a rare and aggressive liver tumor. We report a case study of an 82-year-old elderly gentleman who presented with failure to thrive and ascites. Initially suspected to be cirrhosis, biopsy results eventually concluded angiosarcoma of the liver.

The pan-PPAR agonist lanifibranor improves cardiometabolic health in patients with metabolic dysfunction-associated steatohepatitis.

Lanifibranor, a pan-PPAR agonist, improves liver histology in patients with metabolic dysfunction-associated steatohepatitis (MASH), who have poor cardiometabolic health (CMH) and cardiovascular events as major mortality cause. NATIVE trial secondary and exploratory outcomes (ClinicalTrials.gov NCT03008070) were analyzed for the effect of lanifibranor on IR, lipid and glucose metabolism, systemic inflammation, blood pressure (BP), hepatic steatosis (imaging and histological grading) for all patients of the original analysis.

The role of glucagon-like peptide-1 receptor agonists in metabolic dysfunction-associated steatohepatitis.

Despite its considerable and growing burden, there are currently no Food and Drug Administration-approved treatments for metabolic dysfunction-associated steatotic liver disease or its progressive form, metabolic dysfunction-associated steatohepatitis (MASH). Several glucagon-like peptide-1 receptor agonists (GLP-1RAs) and other agents are in various phases of clinical development for use in MASH; an ideal therapy should reduce liver fat content, improve chronic liver disease, help mitigate metabolic comorbidities and decrease all-cause mortality. Because of interconnected disease mechanisms, metabolic dysfunction-associated steatotic liver disease/MASH often coexists with type 2 diabetes (T2D), obesity and cardiovascular disease.

Phase 2, open-label, rollover study of cenicriviroc for liver fibrosis associated with metabolic dysfunction-associated steatohepatitis.

Background: Cenicriviroc (CVC) is a novel, orally administered antagonist of chemokine receptor types 2/5 that has demonstrated antifibrotic activity in a phase 2b study of patients with NASH. This phase 2, open-label, rollover study investigated the long-term safety and tolerability of CVC in patients with NASH and stage 0-4 liver fibrosis.

Methods: Eligible patients who completed the phase 2 CENTAUR study or reached a predefined endpoint in the phase 3 AURORA study were rolled over and received open-label CVC 150 mg once daily.

AHRR Hypomethylation mediates the association between maternal smoking and metabolic profiles in children.

Background: Tobacco smoking during pregnancy is associated with metabolic dysfunction in children, but mechanistic insights remain limited. Hypomethylation of cg05575921 in the aryl hydrocarbon receptor repressor (AHRR) gene is associated with in utero tobacco smoke exposure. In this study, we evaluated whether AHRR hypomethylation mediates the association between maternal smoking and metabolic dysfunction in children.

A randomized, double-blind, placebo-controlled trial of aldafermin in patients with NASH and compensated cirrhosis.

Background And Aims: Aldafermin, an engineered analog of the human hormone FGF19, improves liver histology in patients with noncirrhotic NASH; however, its efficacy and safety in compensated cirrhosis is unknown. No drug has yet to demonstrate benefit in the compensated NASH population.

Approach And Results: In this multicenter, double-blind, placebo-controlled, phase 2b trial, 160 patients with compensated NASH cirrhosis were randomized to aldafermin 0.

AGA Clinical Practice Update on the Role of Noninvasive Biomarkers in the Evaluation and Management of Nonalcoholic Fatty Liver Disease: Expert Review.

Description: The purpose of this American Gastroenterological Association (AGA) Clinical Practice Update Expert Review is to provide clinicians with guidance on the use of noninvasive tests (NITs) in the evaluation and management of patients with nonalcoholic fatty liver disease (NAFLD). NAFLD affects nearly 30% of the global population and is a growing cause of end-stage liver disease and liver-related health care resource utilization. However, only a minority of all patients with NAFLD experience a liver-related outcome.