What is the Fibrosis‑4 (Fib‑4) index, how is it calculated, and how should its result be interpreted in adults with chronic liver disease?

FIB-4 Index: Calculation, Interpretation, and Clinical Application

What is FIB-4?

The FIB-4 (Fibrosis-4) index is a validated, blood-based calculator that noninvasively assesses the risk of advanced liver fibrosis in patients with chronic liver disease, serving as the recommended first-line screening tool to identify who needs further evaluation or specialist referral. 1, 2

• FIB-4 uses four readily available laboratory values: age (years), AST (aspartate aminotransferase in IU/L), ALT (alanine aminotransferase in IU/L), and platelet count (×10⁹/L), making it simple, inexpensive, and accessible in any clinical setting 1, 2
• The test is calculated using the formula: Age (years) × AST (IU/L) / [Platelet count (×10⁹/L) × √ALT (IU/L)] 2
• FIB-4 outperforms other simple noninvasive tests like APRI for detecting both significant (F2-4) and advanced (F3-4) fibrosis stages 1

How to Interpret FIB-4 Results

Low-Risk Category: FIB-4 <1.3 (or <2.0 if age ≥65 years)

• This reliably excludes advanced fibrosis with >90% negative predictive value 1, 2
• Patients in this category can be reassessed with repeat FIB-4 testing in 2-3 years while implementing lifestyle modifications targeting metabolic risk factors 2, 3
• No immediate specialist referral or additional testing is needed unless clinical features suggest more advanced disease (splenomegaly, thrombocytopenia <150,000/μL, declining albumin, or persistent ALT elevation >2× upper limit of normal despite lifestyle modifications) 3
• For patients with diabetes or multiple metabolic risk factors, consider annual repeat testing rather than every 2-3 years 3

Indeterminate Category: FIB-4 1.3-2.67

• This range captures 30-51% of patients in real-world practice and cannot reliably exclude or confirm advanced fibrosis; second-tier noninvasive testing is mandatory before making management decisions 2, 3
• Many individuals with actual advanced fibrosis fall into this category due to FIB-4's poor sensitivity at rule-in cutoffs 3
• Proceed to vibration-controlled transient elastography (VCTE/FibroScan) as the preferred next step to avoid unnecessary specialist referrals while maintaining high detection rates 1, 3
• If elastography is unavailable, order Enhanced Liver Fibrosis (ELF) testing as an alternative; a sequential FIB-4-then-ELF strategy correctly classifies 88% of cases 3
• The sequential testing approach (FIB-4 followed by elastography or ELF for indeterminate cases) reduces futile referrals by 81% compared to no defined pathway and increases detection of advanced fibrosis 5-fold and cirrhosis 3-fold 3

High-Risk Category: FIB-4 >2.67

• This indicates high probability of advanced fibrosis with 60-80% positive predictive value and warrants immediate hepatology referral for comprehensive evaluation 1, 2, 3
• Consider elastography or liver biopsy for confirmation and staging 2
• Initiate hepatocellular carcinoma surveillance with ultrasound ±AFP every 6 months 3
• Begin aggressive lifestyle modifications targeting 7-10% weight loss and 150-300 minutes weekly moderate-intensity exercise 3
• Implement cardiovascular risk management, as cardiovascular disease is the main driver of morbidity and mortality in NAFLD before cirrhosis develops 3

Disease-Specific Cutoff Variations

Chronic Hepatitis C

• Use cutoffs of <1.45 to exclude advanced fibrosis and >3.25 to identify high probability of advanced fibrosis, with the higher cutoff providing 85-90% specificity 1, 2, 4
• FIB-4 demonstrated an AUROC of 0.84-0.87 for diagnosing cirrhosis in hepatitis C, outperforming APRI 1

Chronic Hepatitis B

• Use cutoffs of <1.0 to exclude and >2.65 to identify advanced fibrosis 4
• FIB-4 has a sensitivity of 69.1% and specificity of 70.5% for advanced fibrosis (≥F3) in chronic hepatitis B 3

NAFLD (Nonalcoholic Fatty Liver Disease)

• Standard cutoffs apply: <1.3 (or <2.0 if age ≥65) for low risk and >2.67 for high risk 1, 4, 5
• FIB-4 showed 95.24% sensitivity at a cutoff of 1.30 and 85% specificity at a cutoff of 2.67 in NAFLD patients 5
• In NAFLD patients with type 2 diabetes, FIB-4 has moderate diagnostic accuracy but may have insufficient negative predictive values when AF prevalence exceeds 30% 6

Alcoholic Liver Disease (ALD)

• FIB-4 has low-to-moderate accuracy in ALD compared to viral hepatitis and NAFLD 4
• High FIB-4 in ALD is associated with significantly high hepatocellular carcinoma incidence and mortality 4

Critical Age-Related Considerations

Age significantly affects FIB-4 values, leading to higher false-positive rates in elderly patients and potential false-negatives in younger patients 2

• Always use the higher cutoff (<2.0) for patients ≥65 years to avoid overestimating fibrosis risk 2, 3
• FIB-4 has reduced accuracy in patients <35 years old due to age-dependent calculations 3
• Patients aged 35-64 years can use the standard low-cutoff of 1.3 with good accuracy 3

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, 3

• High-risk FIB-4 scores were associated with severe liver outcomes for patients with known NAFLD (HR 7.32), other liver disease (HR 11.39), and even no known chronic liver disease (HR 4.05) 7
• Of patients with low-, indeterminate-, and high-risk FIB-4 scores, 2%, 4%, and 20% suffered a severe liver outcome, respectively, during mean follow-up of 2,978 days 7
• In primary care patients without known chronic liver disease, indeterminate (HR 1.41), high (HR 4.65), and persistently high-risk (HR 7.60) FIB-4 strata were associated with higher incidence of severe liver disease 8
• FIB-4 showed ability to predict high-risk varices with cutoffs of 2.87 and 3.91 in cirrhosis patients 4

Common Pitfalls and How to Avoid Them

• Do not assume that a FIB-4 in the low-indeterminate range (e.g., 1.4-1.5) is "close enough" to the low-cutoff of 1.3 to be reassuring; the indeterminate zone exists precisely because disease cannot be excluded in this range 3
• Do not pursue invasive testing (liver biopsy) or specialist referral based solely on imaging findings (e.g., coarsened liver echotexture on ultrasound) when FIB-4 is reassuringly low 3
• Do not wait for symptoms to develop; advanced fibrosis is frequently asymptomatic until decompensation occurs 3
• Do not delay second-tier testing while pursuing prolonged lifestyle-modification trials; timely risk stratification is necessary to determine appropriate monitoring intensity 3
• Diabetes and metabolic syndrome may reduce diagnostic accuracy in NAFLD populations, requiring lower threshold for secondary testing 2

Comparison to Other Noninvasive Tests

• In adults with chronic hepatitis C, VCTE demonstrated superior sensitivity (0.89) and specificity (0.91) compared with FIB-4 (sensitivity 0.87, specificity 0.91) and APRI (sensitivity 0.77, specificity 0.78) for the diagnosis of cirrhosis 1
• The AGA recommends VCTE, if available, rather than other nonproprietary noninvasive serum tests (APRI, FIB-4) to detect cirrhosis in patients with chronic hepatitis C 1
• FIB-4 is recommended as first-line due to simplicity and zero cost, although it may not outperform proprietary tests like ELF or imaging-based elastography 3
• Among nonproprietary markers, FIB-4 <1.45 was better than APRI <0.5 for excluding significant fibrosis (F0-1 vs F2-4), and FIB-4 >3.25 was better than APRI >1.5 for identifying advanced fibrosis (F0-2 vs F3-4) and cirrhosis (F0-3 vs F4) 1

Clinical Performance Metrics

• FIB-4 has an AUROC of approximately 0.77-0.86 for detecting advanced fibrosis, depending on the population studied 2
• The test performs best at ruling out advanced fibrosis (high negative predictive value) rather than confirming it 2
• FIB-4 has limited accuracy in the intermediate range (1.3-2.67), where approximately 30-40% of patients fall, necessitating additional testing 2
• In a meta-analysis of NAFLD patients, FIB-4 showed an AUROC of 0.895 for predicting advanced fibrosis, with 95.24% sensitivity at cutoff 1.30 and 85% specificity at cutoff 2.67 5