Non-Alcoholic Steatohepatitis

Non-Alcoholic Steatohepatitis

Non-alcoholic steatohepatitis (NASH), now more often called metabolic dysfunction-associated steatohepatitis (MASH) under the updated naming, is a progressive form of fatty liver disease. Liver fat comes with inflammation, swollen and damaged liver cells (“ballooning”) and varying degrees of scarring (fibrosis). Simple fatty liver involves fat without much cell injury. NASH is an active disease in which ongoing damage can lead to cirrhosis, liver cancer and liver failure. It is estimated to affect 3% to 5% of people worldwide, and it is rising along with obesity and type 2 diabetes.

NASH develops from several harms at once, often described as the “multiple-hit” hypothesis. Insulin resistance makes the liver produce more fat and export less of it, while oxidative stress, stress in the endoplasmic reticulum and toxins from the gut injure liver cells and switch on inflammation. Chronic inflammation activates stellate cells, which lay down collagen and drive fibrosis forward. Diagnosis usually needs a liver biopsy or validated non-invasive blood test panels. Staging fibrosis is critical for prognosis, because fibrosis stage is the strongest predictor of death from liver disease.

Clinical Relevance to Retatrutide

Retatrutide’s effects on the liver make it a possible treatment for NASH. In phase 2 trials, it cut liver fat sharply, and many participants reached normal liver fat levels on MRI-derived proton density fat fraction scans. Its glucagon receptor activity is thought to be especially relevant, because glucagon signaling increases fat burning in the liver and may reduce the fat load that drives steatohepatitis. Dedicated liver disease trials (Eli Lilly’s SYNERGY/MACELD program) are running and should show whether it can resolve steatohepatitis and slow fibrosis.