MASLD (Fatty Liver)

MASLD, previously termed non-alcoholic fatty liver disease (NAFLD), is defined as steatotic liver disease in the presence of one or more cardiometabolic risk factors and the absence of harmful alcohol intake. ^[1] The spectrum of MASLD ranges from isolated steatosis through metabolic dysfunction-associated steatohepatitis (MASH, previously NASH), fibrosis, cirrhosis and MASH-related hepatocellular carcinoma. ^[1] MASLD is diagnosed based on an ultrasonographic finding of hepatic steatosis together with at least 1 of 5 features of the metabolic syndrome, in the absence of other known causes of steatosis. ^[2]

MASLD is a multisystem, systemic metabolic disorder in which systemic insulin resistance and related metabolic dysfunction play a pathogenic role. ^[3] Metabolic dysregulation caused by obesity, insulin resistance and type 2 diabetes disrupts hepatic metabolism, with de novo lipogenesis and impaired mitochondrial function driving hepatic lipid accumulation and progression from MASLD to MASH. ^[4] Hepatic steatosis results from increased production or reduced clearance of hepatic triglycerides or fatty acids, and can progress to steatohepatitis, a necroinflammatory liver disease. ^[5] MASLD is a sexually dimorphic condition in which estrogens typically protect against and androgens promote disease, and its prevalence is higher in men than in women. ^{[6] [7]}

MASLD affects approximately 30% to 40% of the general adult population globally, including approximately 60% to 70% of individuals with type 2 diabetes and approximately 70% to 80% of those with obesity. ^[2] In a meta-analysis of patients with type 2 diabetes the global pooled prevalence of MASLD was 65.33%, and among those with liver biopsy the prevalence of MASH was 66.44% and of advanced fibrosis 15.49%. ^[8] The Fibrosis-4 index, a scoring system incorporating age, aspartate aminotransferase, alanine aminotransferase and platelet count, and vibration-controlled transient elastography are commonly used to stage hepatic fibrosis in patients with MASLD. ^[2] A stepwise case-finding approach using blood-based scores such as FIB-4 followed by imaging such as transient elastography is used to rule out or in advanced fibrosis, which is predictive of liver-related outcomes. ^[1] Progression to cirrhosis occurs in 3-5% of patients and often takes more than 20 years, and an estimated 20% of patients with NASH will develop cirrhosis. ^[9]

Among MASLD patients the fibrosis stage is the most accurate predictor of mortality, and all histological stages are associated with greater overall mortality in a severity-dependent pattern. ^[11] Cardiovascular disease is the most common cause of death among patients with MASLD, which is also associated with type 2 diabetes, chronic kidney disease and extrahepatic cancers. ^{[12] [3]} First-line treatment involves behavioral modifications including a weight-reducing diet, physical exercise and avoidance of alcohol, along with management of type 2 diabetes, obesity, hypertension and hyperlipidemia. ^[2] Resmetirom and subcutaneous semaglutide are conditionally approved by the US FDA for the treatment of adults with MASH who have moderate to advanced fibrosis. ^[2]