Metabolic Dysfunction-Associated Steatohepatitis (MASH)

MASH, metabolic dysfunction-associated steatohepatitis, is the progressive form of fatty liver disease and a histological diagnosis: fat in hepatocytes plus ballooning degeneration plus lobular inflammation, scored on systems such as the NAFLD activity score, with fibrosis staged separately from F0 to F4. The 2023 nomenclature change replaced non-alcoholic steatohepatitis with MASH and required at least one cardiometabolic criterion, converting a diagnosis of exclusion into one of inclusion. The older acronym NASH still fills the literature and means substantially the same disease.

Resmetirom, a liver-directed thyroid hormone receptor beta agonist, received accelerated approval in March 2024 for non-cirrhotic MASH with moderate to advanced fibrosis, the first drug approved for the condition. Semaglutide 2.4 mg followed on accelerated approval in 2025 after the ESSENCE trial. Accelerated approval is the operative detail: both rest on biopsy surrogates, with outcome trials still running to show the histology translates into fewer cirrhosis events, transplants and deaths.

Regulatory trials use two co-primary endpoints: MASH resolution without worsening fibrosis, and fibrosis improvement without worsening MASH. They capture different things, and only fibrosis stage predicts liver-related mortality reliably. Inflammation can settle while scarring advances, so a drug scoring on one endpoint has not shown the other.

The dominant error is equating liver fat with MASH. Proton density fat fraction on MRI falls with almost any weight loss, and a large percentage cut in liver fat is not resolution of steatohepatitis, which requires ballooning and inflammation to disappear on histology. Biopsy itself is imperfect, with sampling variability between cores and high placebo response on paired reads, which is why single-arm before-and-after histology carries so little weight.