Metabolic Dysfunction-Associated Steatohepatitis (MASH)

A severe and progressive liver disease accompanied by multiple metabolic abnormalities

MASH is the liver’s manifestation of metabolic syndrome characterized by dysregulation of glucose, lipid and bile acid metabolism. MASH is a severe form of metabolic dysfunction-associated steatotic liver disease (MASLD) defined by liver inflammation and injury. It progresses over time and can lead to permanent liver scarring known as fibrosis.

The prevalence of MASLD parallels the obesity and T2DM epidemics affecting approximately 30% of adults worldwide. While MASLD can be relatively harmless, about 1 in 3 will progress to MASH which is associated with a significantly higher risk of death and clinical outcomes such as end-stage liver disease and liver cancer.1,2 MASH is currently the second most common cause for liver transplant in the US and is rapidly rising.3

Insulin resistance and inflammation drives liver fibrosis which decreases survival

Repetitive injury through insulin resistance-driven glucotoxicity and lipotoxicity results in inflammation. Ongoing inflammation in turn can lead to progressive scarring of the liver, called fibrosis. As scarring becomes more severe it progresses to cirrhosis and end-stage liver disease. As fibrosis worsens, long term survival is decreased.

Risk of mortality increases with fibrosis stage

Liver relative to Fibrosis Stage 1
Microscopic picture of liver cells for Fibrosis Stage 1

Fibrosis Stage 1

Liver changing color and disfigured relative to Fibrosis Stage 2
Microscopic picture of liver cells for Fibrosis Stage 2

Fibrosis Stage 2
36% increased risk

Liver changing color and disfigured relative to Fibrosis Stage 3
Microscopic picture of liver cells for Fibrosis Stage 3

Fibrosis Stage 3
154% increased risk

Liver changing color and disfigured relative to Fibrosis Stage 4
Microscopic picture of liver cells for Fibrosis Stage 4

Fibrosis Stage 4
419% increased risk

Advancing treatment and management of MASH treatment through innovative approaches

While the risk of negative outcomes and co-morbidities with MASH increases with worsening fibrosis, it may be insufficient to purely treat fibrosis if the underlying metabolic drivers of injury to the liver persists. We believe therapies for MASH must strive to treat the disease more comprehensively including the metabolic underpinnings and the chronic inflammation that lead to fibrosis and ultimately cirrhosis.

References
1. Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, et al. Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology. 2015;149(2):389-97 e10.
2. Hagstrom H, Nasr P, Ekstedt M, Hammar U, Stal P, Hultcrantz R, et al. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J Hepatol. 2017;67(6):1265-73.
3. Younossi ZM, Stepanova M, Ong J, Trimble G, AlQahtani S, Younossi I, et al. Nonalcoholic Steatohepatitis Is the Most Rapidly Increasing Indication for Liver Transplantation in the United States. Clin Gastroenterol Hepatol. 2021;19(3):580-9 e5