Non-Alcoholic Steatohepatitis

Non-Alcoholic Steatohepatitis

Non-alcoholic steatohepatitis (NASH), now increasingly referred to as metabolic dysfunction-associated steatohepatitis (MASH) under updated nomenclature, is a progressive form of fatty liver disease in which hepatic fat accumulation is accompanied by lobular inflammation, hepatocyte ballooning, and varying degrees of fibrosis. Unlike simple hepatic steatosis, which involves fat deposition without significant cellular injury, NASH represents an active disease state in which ongoing liver damage can lead to cirrhosis, hepatocellular carcinoma, and liver failure. NASH is estimated to affect 3% to 5% of the global population, with prevalence rising in parallel with obesity and type 2 diabetes.

The pathogenesis of NASH involves multiple concurrent insults, often described by the “multiple-hit” hypothesis. Insulin resistance drives increased hepatic lipogenesis and impaired lipid export, while oxidative stress, endoplasmic reticulum stress, and gut-derived endotoxins contribute to hepatocyte injury and activation of inflammatory pathways. Stellate cell activation in response to chronic inflammation leads to collagen deposition and progressive fibrosis. Diagnosis typically requires liver biopsy or validated noninvasive biomarker panels, and staging of fibrosis severity is critical for determining prognosis, as fibrosis stage is the strongest predictor of liver-related mortality.

Clinical Relevance to Retatrutide

Retatrutide has shown promising hepatic effects that position it as a potential therapeutic option for NASH. In phase 2 trials, retatrutide produced marked reductions in liver fat content, with many participants achieving normalization of hepatic fat levels as assessed by MRI-derived proton density fat fraction. The glucagon receptor agonism component of retatrutide is hypothesized to be particularly relevant to NASH, as glucagon signaling enhances hepatic lipid oxidation and may reduce the substrate burden that drives steatohepatitis. Dedicated clinical trials evaluating retatrutide in biopsy-confirmed NASH populations are anticipated to further clarify its potential to resolve steatohepatitis and reduce fibrosis progression.