What is the Fib 4 index (Fibrosis-4 index) and how is it used to assess liver fibrosis in patients with chronic liver diseases?

FIB-4 Index: Definition and Clinical Application

What is the FIB-4 Index?

The FIB-4 (Fibrosis-4) index is a validated, non-invasive blood-based calculator that uses four readily available laboratory values—age, AST, ALT, and platelet count—to assess the risk of advanced liver fibrosis in patients with chronic liver disease. 1, 2

The calculation formula is: (age × AST) / (platelets × √ALT) 2

Primary Clinical Use

FIB-4 serves as the most validated first-line screening tool to identify which patients with chronic liver disease need further evaluation or specialist referral, with its greatest strength being the ability to rule out advanced fibrosis rather than confirm it. 1, 2

The test is:

• Simple and inexpensive, requiring only routine laboratory values 2
• Accessible in any clinical setting without additional cost 2
• Superior to other simple serum markers like APRI for detecting fibrosis 1, 3
• Achieves negative predictive values exceeding 90% at appropriate cutoffs 2

Disease-Specific Cutoff Values and Interpretation

For Non-Alcoholic Fatty Liver Disease (NAFLD)

FIB-4 <1.3 (or <2.0 if age ≥65 years) reliably excludes advanced fibrosis and requires only repeat testing in 2-3 years. 1, 2

• FIB-4 1.3-2.67: Indeterminate zone requiring secondary testing with elastography or Enhanced Liver Fibrosis (ELF) testing 2
• FIB-4 >2.67: High risk for advanced fibrosis, mandating hepatology referral for liver stiffness measurement or biopsy 1, 2

The age-adjusted cutoff of <2.0 for patients ≥65 years is critical to avoid false positives in elderly populations 1, 2

For Viral Hepatitis C

FIB-4 <1.45 excludes advanced fibrosis, while FIB-4 >3.25 suggests advanced fibrosis. 1, 3

FIB-4 was originally validated in hepatitis C and maintains excellent performance in this population 1

For Viral Hepatitis B

FIB-4 cutoffs of <1.0 and >2.65 are used to predict the absence or presence of advanced fibrosis, respectively. 3

Clinical Implementation Algorithm

Who Should Be Screened

Calculate FIB-4 for all patients with:

• NAFLD or metabolic syndrome 2
• Type 2 diabetes or prediabetes 1
• Chronic viral hepatitis 2
• Unexplained elevated liver enzymes 2

Management Based on Results

Low-Risk Patients (FIB-4 <1.3 for age <65, or <2.0 for age ≥65):

• Advanced fibrosis is unlikely with negative predictive value ≥90% 1
• Repeat FIB-4 testing in 2-3 years for patients without diabetes or metabolic risk factors 1
• Re-evaluate after 1-2 years for patients with prediabetes, type 2 diabetes, or two or more metabolic risk factors 1

Indeterminate-Risk Patients (FIB-4 1.3-2.67):

• Reflex to ELF testing or vibration-controlled transient elastography (VCTE/FibroScan) 1, 2
• If ELF <7.7: Continue primary care management with serial monitoring 2
• If ELF ≥9.8: Refer to hepatology for comprehensive evaluation 2
• VCTE cutoffs: ≥8.0-12.0 kPa suggests significant fibrosis; ≥12.0 kPa suggests advanced fibrosis; ≥15.0 kPa suggests cirrhosis 2

High-Risk Patients (FIB-4 >2.67):

• Immediate hepatology referral for further evaluation 1, 2
• Initiate hepatocellular carcinoma surveillance with ultrasound every 6 months 4
• Perform variceal screening via upper endoscopy 2, 4
• Consider disease-specific pharmacotherapy 2

Prognostic Value Beyond Diagnosis

Elevated FIB-4 scores are strongly associated with future liver-related complications, including hepatocellular carcinoma, liver decompensation, liver transplantation, and death. 2

FIB-4 can predict:

• High-risk varices in cirrhosis patients (cutoffs of 2.87 and 3.91) 3
• Long-term survival in hepatocellular carcinoma patients after hepatectomy 3
• High hepatocellular carcinoma incidence and mortality in viral hepatitis, NAFLD, and alcoholic liver disease 3

Important Limitations and Caveats

FIB-4 has several critical limitations that must be considered:

• Age effects: Performs poorly in patients younger than 35 years and requires adjusted cutoffs in those ≥65 years 2, 4
• Disease-specific accuracy: Lower accuracy in alcoholic liver disease and autoimmune hepatitis compared to viral hepatitis and NAFLD 2, 3
• Moderate positive predictive value: Excellent for excluding advanced fibrosis but only moderate for confirming advanced disease 1, 2
• Affected by acute inflammation: Performance can be impaired during acute hepatic inflammation 1
• Limited validation: Not well-validated in certain liver diseases 1

Integration with Other Diagnostic Methods

A two-tier approach (FIB-4 followed by elastography or ELF for indeterminate/high scores) maximizes diagnostic accuracy while minimizing unnecessary testing and liver biopsies. 1, 2

FIB-4 performs best when combined with:

• Vibration-controlled transient elastography (VCTE/FibroScan) 1
• Enhanced Liver Fibrosis (ELF) testing 2
• Magnetic resonance elastography (MRE) for superior diagnostic accuracy 2, 4

This sequential approach reduces unnecessary specialist referrals while identifying patients who truly need advanced evaluation 2