What are the stages and management of liver fibrosis?

Staging of Liver Fibrosis

Fibrosis Staging Systems

Liver fibrosis is staged using standardized histologic scoring systems, with METAVIR (F0-F4) and Ishak (0-6) being the most widely adopted. 1

METAVIR Staging System

• F0: No fibrosis 1
• F1: Portal fibrosis without septa 1
• F2: Portal fibrosis with few septa (significant fibrosis) 2, 1
• F3: Numerous septa without cirrhosis (bridging fibrosis/advanced fibrosis) 2
• F4: Cirrhosis 2, 1

Ishak Staging System

• Stages 0-2: Minimal to mild fibrosis 2, 3
• Stage 3 or higher: Significant fibrosis warranting treatment consideration 2, 3
• Stages 3-4: Advanced fibrosis (bridging fibrosis to cirrhosis) 2

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Non-Invasive Diagnostic Approach

Begin with serum-based biomarkers (FIB-4 or APRI) as first-line screening, followed by elastography for intermediate-risk patients, reserving liver biopsy only for inconclusive cases. 1

First-Line Serum Biomarkers

FIB-4 Score (Preferred)

• Calculation: Based on age, ALT, AST, and platelet count 2
• Low risk (<1.3): 90% negative predictive value for advanced fibrosis; repeat in 2-3 years 3, 1
• Intermediate risk (1.3-2.67): Proceed to transient elastography 3, 1
• High risk (>2.67): 60-80% positive predictive value for advanced fibrosis; refer to hepatology 3, 1

APRI Score

• For Hepatitis B (WHO 2024 Guidelines):
  • >0.5: Identifies significant fibrosis (≥F2) with 6.8% false-negative rate 2
  • >1.0: Identifies cirrhosis (F4) with higher specificity 2
• For general use: Less validated than FIB-4 but useful when FIB-4 unavailable 2

Second-Line Elastography

Transient Elastography (FibroScan)

• <7.0 kPa: Low probability of significant fibrosis 2
• >7.0 kPa: Significant fibrosis (≥F2) likely 2
• 8.0-12.0 kPa: Intermediate risk for advanced fibrosis 3
• >12.5 kPa: Cirrhosis (F4) likely; refer to hepatology 2, 3

Alternative Elastography Methods

• Shear Wave Elastography (SWE): Area under curve 0.88 for advanced fibrosis, 0.91 for cirrhosis; useful when transient elastography unavailable 2
• MR Elastography (MRE): Most accurate imaging-based method but less accessible 2

Proprietary Serum Tests

• Enhanced Liver Fibrosis (ELF) score: Validated for detecting advanced fibrosis when elastography unavailable 2, 4
• Caveat: ELF score more strongly influenced by inflammatory activity than elastography, causing broader overlap in low-moderate fibrosis stages 4

When Liver Biopsy is Required

• Non-invasive tests inconclusive or discordant 1, 5
• Suspected additional liver disease etiologies 5
• Assessing transplantation candidacy 1
• Minimum requirements: 15-20 mm length with ≥11 portal tracts 1

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Management Based on Fibrosis Stage

Minimal Fibrosis (F0-F1 or Ishak ≤2)

Treatment should generally be deferred with annual monitoring, as prognosis without therapy is excellent. 3

Monitoring Strategy

• Annual FIB-4 or transient elastography 3
• Annual liver function tests and complete blood count 3
• Repeat non-invasive assessment in 2-3 years if low-risk scores 1

Consider Treatment Despite Mild Fibrosis If:

• Age >40 years 3
• Male gender 3
• Metabolic syndrome or obesity 3
• Significant necroinflammatory activity 3
• Hepatic steatosis 3
• HIV coinfection 3
• HCV genotypes 2 or 3 (high response rates may justify treatment regardless of fibrosis) 3

Critical Pitfall to Avoid

• Do not assume normal ALT means no disease progression: 14-24% of patients with persistently normal ALT have more-than-portal fibrosis and may progress 3

Significant Fibrosis (F2 or Ishak ≥3)

Treatment should be initiated promptly, as this threshold predicts future liver-related outcomes. 2, 3, 1

• Fibrosis stage F2 or higher is the strongest predictor of liver-related morbidity and mortality 2
• Treatment decisions based on combined assessment of aminotransferases, viral load (if applicable), and fibrosis degree 2

Advanced Fibrosis/Cirrhosis (F3-F4)

Patients require hepatology referral, surveillance for complications, and serial liver stiffness monitoring. 2

Surveillance Requirements

• Hepatocellular carcinoma screening every 6 months 2
• Variceal screening per Baveno criteria 2
• Serial elastography monitoring for clinically significant portal hypertension 2

Imaging for Cirrhosis Detection

• Look for structural changes: Surface nodularity, right lobe atrophy, parenchymal heterogeneity, coarsened echotexture 2
• Doppler ultrasound: Can demonstrate hemodynamic alterations of portal hypertension in long-standing disease 2

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Etiology-Specific Considerations

Chronic Hepatitis B

• WHO 2024 cutoffs prioritize minimizing false negatives to expand treatment access 2
• APRI >0.5 or FibroScan >7.0 kPa: Initiate antiviral therapy in resource-limited settings 2
• Accepts 26.2% false-positive rate to capture 93.2% of patients with significant fibrosis 2

Chronic Hepatitis C

• HCV genotype 1 with mild fibrosis: Treatment often deferred unless favorable predictors (IL28B CC genotype) 3
• HCV genotypes 2 and 3: Consider treating all patients regardless of fibrosis due to high response rates 3

NAFLD/NASH

• FIB-4 is first-line screening tool due to simplicity and low cost 2
• Advanced fibrosis (F3-F4) is key predictor for HCC, decompensation, transplantation, and death 2
• Patients with F3-F4 require serial liver stiffness measurement 2

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Key Clinical Algorithm

1. All patients with chronic liver disease: Calculate FIB-4 or APRI 1
2. Low-risk scores: Repeat in 2-3 years with annual monitoring 3, 1
3. Intermediate scores: Proceed to transient elastography 1
4. High-risk scores or elastography >12 kPa: Refer to hepatology; consider biopsy if management will change 1
5. F2 or higher: Initiate treatment 3, 1
6. F3-F4: Hepatology referral, HCC surveillance, variceal screening, serial elastography 2