How is fibrosis diagnosed and graded?

Diagnosis and Grading of Liver Fibrosis

Liver fibrosis should be diagnosed and graded using a combination of non-invasive methods—specifically transient elastography (FibroScan) and serum biomarkers (FIB-4, NFS, or APRI)—with liver biopsy reserved only for cases where non-invasive tests are inconclusive or when assessing candidacy for transplantation. 1

Initial Assessment Strategy

Non-Invasive Serum Biomarkers (First-Line)

Start with readily available serum-based scoring systems to stratify fibrosis risk 1:

• FIB-4 index (age, platelet count, AST, ALT): Score <1.3 (<2.0 if age >65 years) reliably excludes advanced fibrosis with ≥90% negative predictive value; score >2.67 indicates high risk for advanced fibrosis with 60-80% positive predictive value 1, 2

• NAFLD Fibrosis Score (NFS): Score <-1.455 has 90% sensitivity and 60% specificity to exclude advanced fibrosis; score >0.676 has 67% sensitivity and 97% specificity to identify advanced fibrosis (AUROC 0.85) 1

• APRI (AST/platelet ratio): Useful for detecting significant fibrosis (METAVIR F2-F4) 1

Elastography-Based Imaging (Second-Line for Intermediate Risk)

For patients with intermediate serum biomarker scores, proceed to elastography 1, 3:

• Transient elastography (FibroScan): Liver stiffness >15 kPa strongly suggests compensated advanced chronic liver disease; cutoff of 8.0-9.9 kPa identifies clinically significant fibrosis (≥F2) with 95% sensitivity and 77% specificity (AUROC 0.93) 1, 3, 2

• MR elastography: Currently the most accurate imaging modality for diagnosis and staging of hepatic fibrosis, superior to ultrasound-based elastography, particularly in obese patients 1, 3, 4

• Combination approach: Sequential testing using FIB-4 followed by FibroScan for indeterminate scores is more accurate than either test alone 1, 2

Fibrosis Grading Systems

METAVIR Scoring System (Most Commonly Used)

The METAVIR system grades fibrosis on a 0-4 scale 1:

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

Alternative Histological Scoring Systems

• Ishak scoring system: 0-6 scale (stage 6 = cirrhosis) 1
• Knodell scoring: Used in some centers but less standardized 1

When Liver Biopsy is Indicated

Liver biopsy should be performed only in specific clinical scenarios 1:

• When NASH or advanced liver fibrosis is suspected and non-invasive tests are inconclusive 1
• Assessment for combined heart-liver transplantation in Fontan patients with circulatory failure 1
• When coexisting chronic liver diseases cannot be excluded (autoimmune hepatitis, Wilson's disease, drug-induced hepatitis) 1
• When serum ferritin >1,000 μg/L or elevated liver enzymes in hemochromatosis patients 1
• Not recommended for routine diagnosis of hepatic iron overload or when cirrhosis is already clinically evident 1

Biopsy Technical Requirements

For adequate sampling, obtain 1:

• Minimum length: 15-20 mm (at least 11 portal tracts) 1
• Use 16-18 gauge needle 1
• Perform at least two different passes to minimize sampling error 1
• Staining: Masson trichrome and picrosirius red for fibrosis; orcein staining for maturity assessment 1

Imaging for Cirrhosis Detection

Morphological Features on CT/MRI/Ultrasound

Look for these structural changes indicating advanced disease 1, 3:

• Liver surface nodularity 3
• Right lobe atrophy with caudate and lateral segment hypertrophy 3
• Parenchymal heterogeneity and lattice-like bands of fibrosis (better visualized on MRI than CT) 3
• Portal hypertension signs: ascites (detectable from 100 ml), splenomegaly, varices 3

Critical limitation: Conventional imaging (ultrasound, CT, MRI) only detects very advanced disease and has low sensitivity for early-stage fibrosis 1, 3, 5

Common Pitfalls and Caveats

Elastography Limitations

• Technical failures: FibroScan unreliable in 10-27% of patients, particularly with severe obesity, ascites, narrow intercostal spaces 1, 2
• Confounding factors: Results affected by acute hepatitis, cholestasis, hepatic congestion, recent meals, inflammation 3, 2
• Quality criteria: Require ≥10 successful measurements, ≥60% success rate, interquartile range <30% of median 2

Biopsy Limitations

• Sampling error: Only 1/50,000th of liver examined; 25-60% discordance between biopsies from same patient 2, 5
• Patchy disease: Particularly problematic in Fontan-associated liver disease where fibrosis distribution is extremely heterogeneous 1
• Observer variability: Significant inter- and intra-observer differences in interpretation 1

CT Scan Limitations

• Low sensitivity for diagnosing cirrhosis and non-cirrhotic fibrosis even with multiple morphologic features assessed 6
• Only 62.5% sensitivity for detecting early-stage HCC in cirrhotic patients 6
• Radiation exposure limits repeated use for monitoring 6

Clinical Algorithm

1. All patients with chronic liver disease: Assess with FIB-4 or NFS 1, 2

2. Low-risk scores (FIB-4 <1.3): Repeat surveillance in 2-3 years 2

3. Intermediate scores (FIB-4 1.3-2.67): Proceed to transient elastography 1, 2

4. High-risk scores (FIB-4 >2.67) or elastography >12 kPa: Refer to hepatology; consider biopsy if management will change 1, 2

5. Cirrhosis suspected: Initiate HCC surveillance with ultrasound every 6 months (or MRI/CT if ultrasound inadequate) 1