Steatotic Liver Disease: Pathophysiology and Emerging Pharmacotherapies

Pharmacological Reviews, Год журнала: 2024, Номер 76(3), С. 454 - 499

Опубликована: Янв. 30, 2024

Steatotic liver disease (SLD) displays a dynamic and complex phenotype. Consequently, the metabolic dysfunction-associated steatotic (MASLD)/metabolic steatohepatitis (MASH) therapeutic pipeline is expanding rapidly in multiple directions. In parallel, non-invasive tools for diagnosing monitoring responses to interventions are being studied, clinically feasible findings explored as primary outcomes interventional trials. The realization that distinct subgroups exist under umbrella of SLD should guide more precise personalized treatment recommendations facilitate advancements pharmacotherapeutics. This review summarizes recent updates pathophysiology-based nomenclature outlines both effective pharmacotherapeutics those MASLD/MASH, detailing their mode action current status phase 2 3 clinical Of extensive arsenal MASLD/MASH pipeline, several have been rejected, whereas other, mainly monotherapy options, shown only marginal benefits now tested part combination therapies, yet others still development monotherapies. Although successful drug candidate (or combinations) remains elusive, such approaches will ideally target MASH fibrosis while improving cardiometabolic risk factors. Due urgent need novel strategies potential availability safety tolerability data, repurposing existing approved drugs an appealing option. Finally, it essential highlight and, by extension, MASLD be recognized approached systemic affecting organs, with vigorous implementation interdisciplinary coordinated plans. Significance Statement SLD, including, among others, MASH, considered most prevalent chronic condition than one-fourth global population. aims provide information regarding pathophysiology, diagnosis, management line guidelines Collectively, hoped provided furthers understanding state direct implications stimulates additional research initiatives.

Язык: Английский

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The Interconnection between Hepatic Insulin Resistance and Metabolic Dysfunction-Associated Steatotic Liver Disease—The Transition from an Adipocentric to Liver-Centric Approach

Current Issues in Molecular Biology, Год журнала: 2023, Номер 45(11), С. 9084 - 9102

Опубликована: Ноя. 14, 2023

The central mechanism involved in the pathogenesis of MAFLD is insulin resistance with hyperinsulinemia, which stimulates triglyceride synthesis and accumulation liver. On other side, free fatty acid hepatocytes promotes via oxidative stress, endoplasmic reticulum lipotoxicity, increased secretion hepatokines. Cytokines adipokines cause resistance, thus promoting lipolysis adipose tissue ectopic fat deposition muscles Free acids along cytokines contribute to liver activation numerous signaling pathways. hepatokines, hormone-like proteins, primarily by disturbed impairs pathways, causing metabolic dysregulation ER stress unfolded protein response play significant roles aggravation through apoptosis, inflammatory response, impairment mediated IRE1/PERK/ATF6 pathways upregulation SREBP 1c. Circadian rhythm derangement biological clock desynchronization are related disorders, NAFLD, suggesting genes as a potential target for new therapeutic strategies. This review aims summarize mechanisms hepatic NAFLD development progression.

Язык: Английский

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Advances in management of metabolic dysfunction-associated steatotic liver disease: from mechanisms to therapeutics

Lipids in Health and Disease, Год журнала: 2024, Номер 23(1)

Опубликована: Апрель 2, 2024

Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic that affects over 30% world’s population. For decades, heterogeneity non-alcoholic fatty (NAFLD) has impeded our understanding mechanism and development effective medications. However, a recent change in nomenclature from NAFLD to MASLD emphasizes critical role systemic metabolic dysfunction pathophysiology this therefore promotes progress pharmaceutical treatment MASLD. In review, we focus on underlying abnormality hepatic lipid metabolism patients with MASLD, summarize latest therapeutic medications target disorders.

Язык: Английский

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Dysmetabolic comorbidities and non-alcoholic fatty liver disease: a stairway to metabolic dysfunction-associated steatotic liver disease

Hepatoma Research, Год журнала: 2024, Номер 10, С. 16 - 16

Опубликована: Янв. 1, 2024

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic disease. This term does not describe pathogenetic mechanisms and complications associated with NAFLD. The new definition, Metabolic Dysfunction-associated Steatotic Liver (MASLD), emphasizes relationship between NAFLD cardiometabolic comorbidities. Cardiovascular features, such as arterial hypertension atherosclerosis, are frequently patients MASLD. Furthermore, these have a high risk developing neoplastic diseases, primarily hepatocellular carcinoma, but also extrahepatic tumors, esophageal, gastric, pancreatic cancers. Moreover, several studies showed correlation MASLD endocrine imbalance gut microbiota, systemic inflammation, obesity, insulin resistance play key role in development complications. narrative review aims to clarify evolution from nomenclature evaluate its

Язык: Английский

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Systemic metabolic abnormalities: Key drivers of complications and mortality in MASLD

Journal of Hepatology, Год журнала: 2024, Номер 80(6), С. e246 - e248

Опубликована: Фев. 2, 2024

Язык: Английский

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Type 2 diabetes mellitus and cardiometabolic outcomes in metabolic dysfunction-associated steatotic liver disease population

Diabetes Research and Clinical Practice, Год журнала: 2024, Номер 211, С. 111652 - 111652

Опубликована: Апрель 2, 2024

Язык: Английский

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Fatty Liver Index (FLI) is the best score to predict MASLD with 50% lower cut-off value in women than in men

Biology of Sex Differences, Год журнала: 2024, Номер 15(1)

Опубликована: Май 17, 2024

Metabolic dysfunction-associated steatotic liver disease (MASLD) is defined by the presence of hepatic steatosis, detected on ultrasonography (US) imaging or histology, and at least one criteria for Syndrome diagnosis. Simple non-invasive tests (NITs) have been proposed as an acceptable alternative when US biopsy are not available feasible but validated MASLD. In this observational study, we investigated reliability NITs MASLD detection whether sex-differences in screening methods should be considered.

Язык: Английский

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Efficacy and safety of Resmetirom, a selective thyroid hormone receptor-β agonist, in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD): a systematic review and meta-analysis

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Авг. 26, 2024

Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD) is an important public health problem owing to its high prevalence and associated morbidity mortality secondary progressive cardiovascular events. Resmetirom, a selective thyroid hormone receptor-β agonist has been developed as therapeutic modality for MASLD. This systematic review meta-analysis aimed evaluate the effectiveness safety of resmetirom compared placebo in treatment Eligible studies were systematically identified by screening PubMed, Scopus, Web Science, Cochrane library, Embase, ClinicalTrials.gov from 2014 2024. Only randomized controlled trials comparing efficacy MASLD against included analysis. Meta-analysis was performed using RevMan 5.4 software. Four with low risk bias involving total 2359 participants identified. The metanalysis only three clinical 2234 participants. A significant reduction MRI-proton density fat fraction (MRI-PDFF) 80 mg Resmetirom that [SMD − 27.74 (95% CI 32.05 32.42), p < 0.00001] at 36–52 weeks well 12–16 30.92 36.44 25.40), 0.00001]. With 100 dose 36.05 40.67 31.43), 36.89 40.73 33.05), observed. LDL-c triglyceride, lipoproteins. enzymes. There FT4 increase SHBG sex steroids placebo. no major difference overall emergent adverse events [OR 1.55 0.84 2.87), 1.13 0.78 1.63), doses However, gastrointestinal diarrhoea nausea occurred ≥ 10% group 12 week. showed modest treating MRI-PDFF, LDL-c, lipoproteins, enzymes NASH biomarkers without concerns. Larger long-term RCTs may further confirm this promising outcomes use

Язык: Английский

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Metabolic dysfunction-associated steatotic liver disease: Evolution of the final terminology

European Journal of Internal Medicine, Год журнала: 2024, Номер 124, С. 35 - 39

Опубликована: Апрель 22, 2024

The medical term nonalcoholic fatty liver disease (NAFLD) was coined in 1986 for a condition that has since become the most prevalent disorder worldwide. In last 3 years, global professional community launched 2 consecutive efforts to purge NAFLD from dictionary and recommended new terms based on pathophysiology rather than distinction similar conditions featuring steatosis. A consensus by renowned clinical scholars primarily residing Asian-Pacific region introduced metabolic dysfunction-associated (MAFLD) as name replace 2020. 2023, nomenclature classification resulting steatotic (MASLD) developed large expert panel under auspices of leading societies Europe Americas. These marked rapid shifts have garnered attention many researchers clinicians across globe due multilevel impact frequent potentially progressive chronic both adult pediatric populations. proposed terminologies differ several ways but they more common differences. They capture key features associated with cardiometabolic risk factors significant all-cause liver-related mortality. framework MASLD incorporated innovative aspects MAFLD while conceptual disparities remain work progress, should focus insights into pathogenesis, outcome trajectories, prevention, treatment. Here, some these challenges are discussed facilitate this process.

Язык: Английский

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Pharmacotherapeutic options for metabolic dysfunction-associated steatotic liver disease: where are we today?

Expert Opinion on Pharmacotherapy, Год журнала: 2024, Номер 25(9), С. 1249 - 1263

Опубликована: Июнь 12, 2024

Metabolic dysfunction-associated steatotic liver disease (MASLD) is defined by hepatic steatosis and cardiometabolic risk factors like obesity, type 2 diabetes, dyslipidemia. Persistent metabolic injury may promote inflammatory processes resulting in steatohepatitis (MASH) fibrosis. Mechanistic insights helped to identify potential drug targets, thereby supporting the development of novel compounds modulating drivers.

Язык: Английский

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