Emerging and Established Therapeutic Approaches for Nonalcoholic Fatty Liver Disease

Brown, Emily, Hydes, T ORCID: 0000-0002-7768-6886, Hamid, A and Cuthbertson, DJ ORCID: 0000-0002-6128-0822 (2021) Emerging and Established Therapeutic Approaches for Nonalcoholic Fatty Liver Disease. CLINICAL THERAPEUTICS, 43 (9). pp. 1476-1504.

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Abstract

<h4>Purpose</h4>Nonalcoholic fatty liver disease (NAFLD), more recently referred to as metabolic-associated fatty liver disease, refers to a disease spectrum ranging from hepatic steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis, associated with hepatic complications (including liver fibrosis, cirrhosis, and hepatocellular carcinoma) and extrahepatic complications (particularly cardiometabolic complications, including type 2 diabetes and cardiovascular disease). Treatment options include lifestyle interventions (dietary modification and physical activity programs) and pharmacologic interventions. Treatment aims should be broad, with a hepatic focus (to improve/reverse hepatic inflammation, fibrosis, and steatohepatitis), ideally with additional extrahepatic effects affecting metabolic co-morbidities (eg, insulin resistance, glucose dysregulation, dyslipidemia), causing weight loss and affording cardiovascular protection. NASH and fibrosis represent the main histopathological features that warrant treatment to prevent disease progression. Despite a paucity of established treatments, the array of potential molecular targets, pathways, and potential treatments is continually evolving. The goal of this article was to provide a narrative review summarizing the emerging and more established therapeutic options considering the complex pathophysiology of NAFLD and the important long-term sequelae of this condition.<h4>Methods</h4>The literature was reviewed by using PubMed, conference abstracts, and press releases from early-phase clinical studies to provide an overview of the evidence.<h4>Findings</h4>As understanding of the pathophysiology of NASH/NAFLD evolves, drugs with different mechanisms of action, targeting different molecular targets and aberrant pathways that mediate hepatic steatosis, inflammation, and fibrosis, have been developed and are being tested in clinical trials. Pharmacologic therapies fall into 4 main categories according to the molecular targets/pathways they disrupt: (1) meta-bolic targets, targeting insulin resistance, hepatic de novo lipogenesis, or substrate utilization; (2) inflam-matory pathways, inhibiting inflammatory cell recruitment/signaling, reduce oxidative/endoplasmic reticulum stress or are antiapoptotic; (3) the liver-gut axis, which modulates bile acid enterohepatic circulation/signaling or alters gut microbiota; and (4) antifibrotic targets, targeting hepatic stellate cells, decrease collagen deposition or increase fibrinolysis.<h4>Implications</h4>Lifestyle modification must remain the cornerstone of treatment. Pharmacologic treatment is reserved for NASH or fibrosis, the presence of which requires histopathological confirmation. The disease complexity provides a strong rationale for combination therapies targeting multiple pathways simultaneously.

Item Type:	Article
Uncontrolled Keywords:	fibrosis, insulin resistance, NAFLD, NASH, nonalcoholic steatohepatitis
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences
Depositing User:	Symplectic Admin
Date Deposited:	27 Jan 2022 10:22
Last Modified:	18 Jan 2023 21:14
DOI:	10.1016/j.clinthera.2021.07.013
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3147643