MASH/NASH Diagnosis and Fibrosis Staging
MASH/NASH is a histologic diagnosis defined by ≥5% hepatic steatosis with inflammation and hepatocyte ballooning, and can occur at any fibrosis stage from F0 to F4—the fibrosis score itself does not indicate the presence or absence of MASH/NASH, but rather quantifies the degree of scarring that has resulted from the inflammatory process. 1
Understanding the Distinction Between MASH/NASH and Fibrosis Stage
The critical concept is that MASH/NASH and fibrosis staging are separate but related assessments:
- MASH/NASH is diagnosed by the presence of steatohepatitis (fat accumulation plus inflammation and hepatocyte injury), which can exist at any fibrosis stage 1
- Fibrosis staging (F0-F4) quantifies the degree of liver scarring that has accumulated as a consequence of ongoing inflammation 1, 2
Fibrosis Stage Classification
The METAVIR/Scheuer fibrosis staging system classifies liver scarring as follows 1, 2:
- F0: No fibrosis
- F1: Mild fibrosis (portal fibrosis without septa)
- F2: Moderate/significant fibrosis (portal fibrosis with few septa)
- F3: Severe/advanced fibrosis (numerous septa without cirrhosis)
- F4: Cirrhosis
Clinical Significance of Fibrosis Stages in MASH/NASH
Patients with MASH/NASH can have any fibrosis stage from F0 to F4, but the presence and severity of fibrosis fundamentally changes prognosis and management 1:
Clinically Significant Fibrosis (≥F2)
- Between 12-20% of people with type 2 diabetes have clinically significant fibrosis (≥F2) 1
- F2 or greater represents the threshold where fibrosis becomes clinically significant and is associated with increased risk of progression to cirrhosis 1
- The FDA-approved medication resmetirom specifically targets patients with MASH and F2-F3 fibrosis (moderate to advanced fibrosis without cirrhosis) 1
Advanced Fibrosis (≥F3)
- F3 fibrosis requires hepatocellular carcinoma (HCC) surveillance every 6 months with abdominal ultrasound, as HCC risk is substantially elevated even before cirrhosis develops 3
- Patients with F3 require evaluation for portal hypertension including upper endoscopy for variceal screening 3
- All F3 patients should be referred to hepatology for specialized management 3
Cirrhosis (F4)
- F4 represents cirrhosis and carries the highest risk of liver-related complications including decompensation and HCC 1
- MASH is a leading cause of hepatocellular carcinoma and liver transplantation in the U.S., with transplant waiting lists overrepresented by people with type 2 diabetes 1
Noninvasive Assessment in Clinical Practice
Since liver biopsy is impractical for widespread screening, noninvasive tests (NITs) are used to identify patients with clinically significant fibrosis who likely have MASH 1:
Recommended Screening Algorithm
For patients with metabolic risk factors (obesity, diabetes, metabolic syndrome) 1, 4:
- Calculate FIB-4 first using routine labs (AST, ALT, platelet count, age) 1, 4
- If FIB-4 ≥1.3, proceed to additional testing with vibration-controlled transient elastography (VCTE/FibroScan) or enhanced liver fibrosis (ELF) score 1, 4
- Use the following thresholds to identify F2-F3 fibrosis (the treatment-eligible population for resmetirom) 1:
- VCTE: 10-15 kPa (suggests F2-F3)
- MRE: 3.3-4.2 kPa (suggests F2-F3)
- ELF score: 9.2-10.4 (suggests F2-F3, though 9.8 cutoff recommended when used in isolation to reduce false positives)
Excluding Cirrhosis
Patients with the following findings likely have cirrhosis (F4) and should be excluded from resmetirom therapy 1:
- VCTE >20 kPa
- MRE >5 kPa
- ELF >11.3
- Platelet count <140,000/μL
- Clinical or imaging evidence of portal hypertension
Key Clinical Pitfall
The most common error is conflating the presence of MASH/NASH with a specific fibrosis stage. MASH/NASH is diagnosed by histologic criteria showing steatohepatitis (≥5% steatosis with inflammation and ballooning), which can occur at any fibrosis stage 1. The fibrosis score (F0-F4) quantifies the scarring that has accumulated as a consequence of ongoing inflammation, with F2-F3 representing the "sweet spot" where treatment with medications like resmetirom is indicated—advanced enough to warrant intervention but not yet cirrhotic 1.