What is MASH?
MASH stands for Metabolic dysfunction-Associated SteatoHepatitis, a progressive liver disease characterized by fat accumulation, inflammation, and liver cell injury that can lead to advanced fibrosis and cirrhosis.
Disease Definition and Nomenclature
MASH represents the progressive subtype of metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic steatohepatitis (NASH) 1. The terminology evolved from NASH to MASH to better reflect the metabolic underpinnings of the disease 1.
Clinical Significance and Risk Stratification
The most clinically important subset is "at-risk MASH," defined as MASH with moderate to advanced fibrosis (stages F2-F3), as this population faces the highest risk of progression to cirrhosis and liver-related complications 1. The American Association for the Study of Liver Diseases (AASLD) identifies this at-risk MASH population as most likely to benefit from treatment intervention 1.
Key Disease Features:
- Histological criteria: Steatohepatitis with hepatocyte ballooning and inflammation, accompanied by fibrosis 1
- Fibrosis staging: Ranges from F0 (no fibrosis) to F4 (cirrhosis), with F2-F3 representing moderate to advanced noncirrhotic fibrosis 1
- Progressive nature: Can lead to major adverse liver-related outcomes (MALOs) including cirrhosis, hepatocellular carcinoma, and liver failure 1
Treatment Landscape
FDA-Approved Therapy
On March 14,2024, the FDA granted conditional approval to resmetirom, marking the first approved drug specifically for treating MASH with moderate to advanced fibrosis (F2-F3) without cirrhosis 1. This represents a landmark achievement after more than two decades of research 1.
Resmetirom Indication:
- Approved for: Adults with noncirrhotic NASH/MASH with moderate to advanced liver fibrosis (F2-F3 stages) 1
- Used in conjunction with: Diet and exercise 1
- Dosing: Weight-based—80 mg for patients <100 kg, 100 mg for patients ≥100 kg 1
- Exclusions: Patients with cirrhosis and those with early fibrosis (F0-F1) 1
Regulatory Endpoints
The FDA granted conditional approval based on histological endpoints from the MAESTRO-NASH phase 3 trial 1. Full FDA approval requires demonstration of favorable impact on clinical outcomes, but conditional approval can be granted when prespecified histological endpoints are met: resolution of steatohepatitis without worsening of fibrosis, OR ≥1 stage improvement in fibrosis without worsening of steatohepatitis 1.
Diagnostic Considerations
Histological Assessment
Liver biopsy remains important for MASH drug development and diagnosis, though non-invasive biomarkers are being developed 1. Current clinical trials utilize composite or dual primary endpoints assessing both steatohepatitis resolution and fibrosis improvement 1.
Common Pitfalls:
- Do not confuse MASH with MASH units: The acronym historically referred to Mobile Army Surgical Hospital (a military field hospital concept) 2, 3, but in current hepatology literature, MASH exclusively refers to the liver disease
- Terminology transition: Clinicians must recognize that NASH and MASH refer to the same disease entity, with MASH being the updated nomenclature 1
Future Directions
Multiple drugs are in phase III development with varying endpoint designs, including lanifibranor, semaglutide, and efruxifermin 1. The field is moving toward non-invasive biomarkers to potentially replace liver biopsy as surrogate endpoints, though regulatory endorsement is still pending 1.