Metabolic dysfunction associated steatotic liver disease: from pathogenesis to clinical cardio-metabolic implications

Overview

Metabolic dysfunction Associated Steatotic Liver Disease (MASLD) is a multisystemic disease, that has become a public-health problem worldwide. Affects approximately 30–40 % of the general adult population globally, including approximately up to 70 % of individuals with type 2 diabetes and 80 % of those with obesity. Metabolic dysfunction is key to the pathogenesis and consequences of MASLD. The clinical burden of MASLD consists mainly of liver-related disease and death and high rates of fatal and nonfatal cardiovascular disease, chronic kidney disease, type 2 diabetes, and certain extrahepatic cancers, especially extrahepatic gastrointestinal cancers. Cardiovascular disease is the leading cause of death, followed by extrahepatic cancers, and liver-related complications (liver failure, decompensations, ascites, encephalopathy) and HCC. Blood-based biomarkers of fibrosis and transient elastography are used for screening and monitoring of liver disease progression and regression and predict long-term liver-related and extrahepatic events. First-line treatment of MASLD involves lifestyle modifications (hypocaloric, low-carbohydrate and low-fat diets, physical exercise, avoidance of alcohol). Comprehensive management of shared underlying metabolic substrate and complex metabolic conditions is crucial for hepatic and cardiovascular outcomes. There is a pressing need for drugs to treat MASLD and its more severe form, metabolic dysfunction–associated steatohepatitis (MASH). Resmetirom, a liver-directed, thyroid hormone receptor beta –⁠ selective agonist, was the first drug conditionally approved by the Food and Drug Administration for treating adults with noncirrhotic MASH and moderate-to-advanced fibrosis. Incretin-based drugs (especially semaglutide at a dose of 2.4 mg per week) and other metabolism-based pharmacotherapies are showing promise as therapeutic options not only for steatotic liver disease but also for cardiovascular–kidney–metabolic complications that are strongly related to MASLD. Semaglutide is conditional approved by US Food and Drug Administration for the treatment of adults with MASH in stage of significant and advanced fibrosis.

Keywords:

semaglutide – resmetirom – inkretin-based drugs – metabolic dysfunction associated steatotic liver disease (MASLD) – steatohepatitis (MASH)