What are the diagnostic criteria and management options for Non-Alcoholic Steatohepatitis (NASH)?

Diagnostic Criteria and Management of Non-Alcoholic Steatohepatitis (NASH)

Liver biopsy remains the gold standard for diagnosing NASH as non-invasive diagnostic methods have limited accuracy for distinguishing NASH from simple steatosis. 1

Diagnostic Approach to NASH

Initial Evaluation

• Exclude competing etiologies for liver disease:

  • Viral hepatitis (HBV, HCV)
  • Autoimmune liver disease
  • Genetic hemochromatosis
  • Wilson's disease
  • Alpha-1 antitrypsin deficiency
  • Alcoholic liver disease (exclude alcohol consumption >21 drinks/week for men, >14 drinks/week for women) 1

• Laboratory tests:

  • Liver enzymes (ALT, AST)
  • Serum ferritin and iron saturation
  • Autoantibodies (ANA, ASMA)
  • Viral hepatitis serologies
  • Fasting glucose, lipid profile

Diagnosis of Hepatic Steatosis

1. First-line imaging: Abdominal ultrasonography 1

   • Widely available and cost-effective
   • Limited sensitivity for steatosis <20% or in patients with BMI >40 kg/m²

2. Alternative imaging options:

   • Controlled Attenuation Parameter (CAP)
   • Unenhanced CT
   • MR Spectroscopy (MRS)
   • MRI-PDFF (Proton Density Fat Fraction)

3. Serum biomarker panels when imaging is not feasible:

   • Fatty Liver Index (FLI): ≥60 diagnoses NAFLD, <30 excludes NAFLD
   • NAFLD Liver Fat Score (NLFS): >-0.64 indicates steatosis
   • Hepatic Steatosis Index (HSI): ≥36 indicates steatosis, <30 excludes steatosis

Diagnosis of NASH

Liver biopsy is required for definitive diagnosis of NASH 1

Histological criteria for NASH include:

• ≥5% hepatic steatosis
• Hepatocellular injury evidenced by:
  • Ballooning degeneration
  • Lobular inflammation
  • Apoptotic bodies 2

Non-invasive methods for NASH diagnosis have limitations:

• Cytokeratin-18 fragments: moderate accuracy (66% sensitivity, 82% specificity) 1
• Multiparametric MRI indices: promising but not yet validated for clinical use

Assessment of Liver Fibrosis

1. Non-invasive fibrosis assessment:

   • Serum biomarker panels:

     • NAFLD Fibrosis Score (NFS)
     • FIB-4 (Fibrosis-4)
     • Enhanced Liver Fibrosis (ELF) panel

   • Elastography techniques:

     • Transient elastography (FibroScan)
     • Point shear wave elastography
     • 2D shear wave elastography
     • Magnetic resonance elastography (MRE)

   These tests perform best at distinguishing advanced fibrosis (F3-F4) from non-advanced fibrosis, with higher negative predictive values than positive predictive values 1

2. Liver biopsy for fibrosis staging when:

   • Non-invasive tests show indeterminate or high risk of advanced fibrosis
   • Competing etiologies cannot be excluded
   • Other features require histological assessment

Management of NASH

Lifestyle Modifications

• Dietary recommendations:

  • Mediterranean-style diet
  • Caloric restriction (500-1000 kcal/day reduction)
  • Target weight loss:
    • 3-5% to improve steatosis
    • 7-10% to improve inflammation and liver enzymes

    • 10% to improve fibrosis 3

• Physical activity:

  • 150-200 minutes/week of moderate-intensity aerobic exercise
  • Combination of aerobic and resistance training 3

Pharmacological Management

• First-line option for non-cirrhotic NASH with significant fibrosis (stage ≥2):

  • Resmetirom 3

• For patients with comorbidities:

  • Type 2 diabetes/obesity: GLP-1 receptor agonists (semaglutide, liraglutide)
  • Type 2 diabetes/heart failure/CKD: SGLT2 inhibitors
  • Dyslipidemia: Statins (safe in compensated cirrhosis) 3

Bariatric Surgery

• Consider for non-cirrhotic NASH in patients meeting criteria for bariatric surgery
• Requires careful evaluation by multidisciplinary team for patients with compensated cirrhosis 3

Monitoring

• Liver enzymes every 3 months
• Imaging every 6-12 months
• Consider repeat biopsy after 1-2 years of therapy to assess histological response
• HCC surveillance with ultrasound every 6 months for patients with advanced fibrosis or cirrhosis
• Non-invasive fibrosis assessment every 1-2 years 3

Common Pitfalls to Avoid

1. Relying solely on ALT/AST levels - normal values don't exclude NASH
2. Overreliance on non-invasive tests for NASH diagnosis - they cannot definitively diagnose NASH
3. Inadequate exclusion of alcohol consumption - thorough alcohol history is essential
4. Failure to assess for metabolic comorbidities - diabetes, obesity, dyslipidemia increase NASH risk
5. Inadequate monitoring - NASH can progress silently to advanced fibrosis

By following this structured approach to diagnosis and management, clinicians can effectively identify and treat patients with NASH, potentially preventing progression to cirrhosis and its complications.