What is Metabolic Dysfunction Associated Steatohepatitis (MASH)?

Metabolic Dysfunction-Associated Steatohepatitis (MASH)

Metabolic dysfunction-associated steatohepatitis (MASH) is the progressive inflammatory form of metabolic dysfunction-associated steatotic liver disease (MASLD) characterized by hepatocellular ballooning and lobular inflammation, which can lead to fibrosis, cirrhosis, and hepatocellular carcinoma if left untreated. 1

Definition and Classification

MASH is part of the spectrum of MASLD (previously known as non-alcoholic fatty liver disease or NAFLD), which is defined as:

• Steatotic liver disease (SLD) in the presence of one or more cardiometabolic risk factors
• Absence of harmful alcohol intake (defined as <20g/day for women and <30g/day for men)

The MASLD spectrum includes:

• Simple steatosis (MASL)
• Steatohepatitis (MASH)
• Fibrosis
• Cirrhosis
• MASH-related hepatocellular carcinoma (HCC)

Pathophysiology

MASH develops through:

• Alterations in hepatic lipid metabolism
• Insulin resistance
• Chronic inflammation (metaboinflammatory state)
• Hepatocellular injury manifesting as ballooning and lobular inflammation 2

Diagnostic Features

MASH is diagnosed when the following are present:

• Hepatic steatosis (identified by imaging or biopsy)
• At least one cardiometabolic risk factor
• Histological evidence of:
  • Hepatocellular ballooning
  • Lobular inflammation 1

Risk Factors and Associated Conditions

MASH is strongly associated with:

• Type 2 diabetes mellitus
• Obesity
• Metabolic syndrome components
• Insulin resistance 3

Disease Progression and Outcomes

The progression of MASH correlates with disease severity:

• Mortality risk increases with fibrosis stage, from 0.14/100 person-months at F0-F1 to 4.62/100 person-months with decompensated cirrhosis
• Risk of progression to cirrhosis is significantly higher in patients with F3 fibrosis (HR 18.66) and F2 fibrosis (HR 3.74) compared to F0-F1
• Patients with type 2 diabetes (67.9%) and hypertension (73.9%) have higher rates of progression to adverse outcomes 3

Diagnostic Approach

Non-invasive testing is increasingly used for diagnosis and monitoring:

• Blood-based scores (FIB-4)
• Imaging techniques (transient elastography)
• Liver enzyme tests

However, liver biopsy remains the gold standard for definitive diagnosis of MASH, showing:

• Steatosis
• Hepatocellular ballooning
• Lobular inflammation 1

Management

Treatment strategies for MASH focus on:

1. Lifestyle modifications:

   • Weight loss (7-10% of body weight)
   • Mediterranean diet
   • Regular physical exercise
   • Avoidance of alcohol consumption 2

2. Management of comorbidities:

   • Use of incretin-based therapies (semaglutide, tirzepatide) for T2D or obesity 2
   • Bariatric surgery for patients with obesity 1

3. MASH-targeted pharmacotherapy:

   • Resmetirom for non-cirrhotic MASH with significant fibrosis (stage ≥2) - the first FDA-approved therapy for MASH 1, 4
   • No specific MASH-targeted pharmacotherapy is currently recommended for cirrhotic stage 1

4. Management of MASH-related cirrhosis:

   • Adaptations of metabolic drugs
   • Nutritional counseling
   • Surveillance for portal hypertension and HCC
   • Liver transplantation in decompensated cirrhosis 1

Emerging Therapies

Several therapeutic approaches are under investigation:

• PPAR agonists
• Farnesoid X receptor (FXR) agonists
• Antifibrotic agents
• Fatty acid synthase inhibitors 2, 4

Clinical Challenges

Key challenges in MASH management include:

• Significant underdiagnosis (approximately 75% of patients remain undiagnosed) 5
• Limited approved pharmacological options
• Difficulty in sustaining lifestyle modifications
• Need for personalized therapeutic approaches based on predominant pathophysiological mechanisms 2

MASH represents a significant global health challenge with increasing prevalence and substantial morbidity and mortality, requiring early identification and comprehensive management to prevent progression to end-stage liver disease.