What are the Enhanced Liver Fibrosis (ELF) test and Fibrosis-4 (FIB-4) test used for in patients with liver disease?

ELF Test and FIB-4 Test: Clinical Applications and Interpretation

What These Tests Are

The FIB-4 and ELF tests are blood-based noninvasive tools used to assess liver fibrosis severity in patients with chronic liver disease, with FIB-4 serving as the recommended first-line screening test and ELF as a confirmatory second-tier test when FIB-4 results are indeterminate. 1

FIB-4 (Fibrosis-4 Index)

• FIB-4 is calculated using four readily available laboratory values: age, AST, ALT, and platelet count, making it simple, inexpensive, and accessible in any clinical setting without requiring specialized equipment 1, 2
• The formula is: (Age × AST) / (Platelet count × √ALT) 1, 2
• FIB-4 is the most validated and recommended first-line noninvasive test for identifying patients at low or high probability of advanced fibrosis across multiple chronic liver diseases including NAFLD/MASLD, viral hepatitis, and metabolic liver disease 1, 2

ELF (Enhanced Liver Fibrosis) Test

• The ELF test combines three serum markers of extracellular matrix metabolism: hyaluronic acid (HA), tissue inhibitor of metalloproteinase-1 (TIMP-1), and amino-terminal propeptide of type III procollagen (PIIINP) using an automated logarithmic algorithm 1, 3
• ELF demonstrates superior diagnostic performance compared to simple fibrosis scores, with an AUROC of 0.90 for advanced fibrosis 3
• ELF is recommended as a second-line confirmatory test when FIB-4 falls in the indeterminate range, improving diagnostic accuracy and reducing unnecessary liver biopsies 1, 2, 4

Clinical Interpretation: FIB-4 Cutoff Values

For NAFLD/MASLD Patients

• FIB-4 <1.3 (or <2.0 if age ≥65 years) reliably excludes advanced fibrosis with >90% negative predictive value, allowing patients to be managed in primary care with reassessment every 2-3 years 1, 2
• FIB-4 1.3-2.67 represents an indeterminate zone requiring secondary testing with elastography (transient elastography/FibroScan) or ELF test 1, 2
• FIB-4 >2.67 indicates high risk for advanced fibrosis and warrants immediate hepatology referral for comprehensive evaluation 1, 2

Age-Adjusted Considerations

• Higher cutoffs are necessary for patients ≥65 years (use <2.0 to rule out advanced fibrosis rather than <1.3) to avoid overestimating fibrosis risk due to age-dependent calculations 1, 2
• FIB-4 has not been validated in patients <35 years of age, and results should be interpreted with caution in this population 1

Clinical Interpretation: ELF Cutoff Values

• ELF <7.7 has a sensitivity of 0.93 for excluding fibrosis, allowing patients to continue primary care management with serial monitoring 1, 5
• ELF 7.7-9.8 represents an intermediate risk zone requiring clinical correlation and consideration of additional testing 2
• ELF ≥9.8 indicates high risk for advanced fibrosis with specificity of 0.86, prompting hepatology referral for comprehensive evaluation including consideration of liver biopsy, hepatocellular carcinoma surveillance, and variceal screening 1, 2, 4

Sequential Testing Strategy: The Recommended Approach

Guidelines from multiple societies recommend a two-step sequential approach starting with FIB-4, followed by ELF or elastography for indeterminate results, which improves diagnostic accuracy while minimizing unnecessary referrals and invasive procedures. 1, 2

Step 1: Calculate FIB-4 for All At-Risk Patients

• All patients with NAFLD, metabolic syndrome, type 2 diabetes, chronic viral hepatitis, or unexplained elevated liver enzymes should have FIB-4 calculated as initial screening 2
• This first-line test costs nothing and uses routine laboratory values already available in most clinical settings 1, 2

Step 2: Risk Stratification Based on FIB-4

• Low-risk patients (FIB-4 <1.3 or <2.0 if ≥65 years) can be reassessed in 2-3 years with continued primary care management focusing on lifestyle modifications 1, 2
• Indeterminate-risk patients (FIB-4 1.3-2.67) require reflex to ELF testing or transient elastography to improve diagnostic accuracy 1, 2
• High-risk patients (FIB-4 >2.67) should be referred directly to hepatology for comprehensive evaluation 1, 2

Step 3: ELF Testing for Indeterminate FIB-4

• When FIB-4 falls in the indeterminate range, automatically perform ELF testing to reduce unnecessary specialist referrals and improve diagnostic precision 2, 4
• The combination of FIB-4 ≥1.30 and ELF ≥9.8 showed 67.86% sensitivity, 90.40% specificity, and 83.64% accuracy for predicting advanced fibrosis in a real-world MASLD cohort 4
• This sequential approach excluded 71.8% of patients from unnecessary liver biopsies while maintaining diagnostic accuracy 4

Clinical Benefits of Sequential Testing

• Sequential testing with FIB-4 followed by ELF or transient elastography improves sensitivity and specificity to rule in or rule out advanced fibrosis compared to single tests alone 1
• A FIB-4+ELF care pathway reduced referrals of patients with mild disease by 81% while increasing detection of advanced fibrosis 5-fold in UK primary care settings 1
• Sequential testing lowers the uncertainty area to <10% compared to approximately one-third of patients having indeterminate results with single tests 1

Diagnostic Performance Comparison

FIB-4 Performance

• FIB-4 has an AUROC of 0.80 for advanced fibrosis in NAFLD, with high negative predictive value (>90%) but modest positive predictive value (<70%) 1
• FIB-4 performs best at ruling out advanced fibrosis rather than confirming it, making it ideal as a first-line screening tool 2
• FIB-4 outperforms APRI for detecting both F2-F4 and F3-F4 fibrosis stages 2

ELF Performance

• ELF demonstrates AUROC of 0.83-0.90 for detecting advanced fibrosis, with sensitivity of 80%, specificity of 90%, positive predictive value of 71%, and negative predictive value of 94% 1, 3
• ELF maintains diagnostic accuracy across all fibrosis stages from early to advanced disease in Japanese and Western cohorts 6, 7
• ELF has higher diagnostic accuracy for cirrhosis (F4) than FIB-4, particularly in elderly populations 6
• ELF is less affected by age compared to FIB-4, with median ELF scores not differing by age in F2, F3, and F4 stages, while FIB-4 increases with age across all fibrosis stages 6

Prognostic Value Beyond Diagnosis

Predicting Clinical Outcomes

• Elevated FIB-4 and ELF scores are strongly associated with future liver-related complications including hepatocellular carcinoma, liver decompensation, liver transplantation, and death 1, 2
• Patients with ELF ≥11.27 have significantly increased risk of clinical events with a C-statistic of 0.68 for predicting onset of decompensation 1, 8
• FIB-4 and NFS accurately predict occurrence of liver events (AUROC 0.86 and 0.81 respectively) and overall mortality in biopsy-proven NAFLD cohorts 1

Monitoring Disease Progression

• Changes over time in FIB-4 and NFS are significantly associated with fibrosis progression, with cross-validated C-statistics of 0.81-0.82 for detecting progression to advanced fibrosis 1
• Repeated measurements of noninvasive tests can refine stratification of risk for liver-related events, though optimal timeframes between assessments require further validation 1
• Longitudinal assessment of fibrosis should be considered every 6 months to 1 year in patients with ≥F2 fibrosis and every 1-2 years in those with F0 or F1 fibrosis 1

Important Limitations and Caveats

FIB-4 Limitations

• FIB-4 has lower accuracy in alcoholic liver disease and autoimmune hepatitis compared to viral hepatitis and NAFLD 2
• Older age affects FIB-4 diagnostic accuracy, requiring adjusted cutoffs (≥2.0 for ruling out advanced fibrosis in patients >65 years) 1
• FIB-4 has only moderate positive predictive value for confirming advanced disease despite excellent negative predictive value, leading to false positive results particularly in NAFLD compared to viral hepatitis 1, 2
• FIB-4 may suggest lower performance in obese patients and diabetic patients, where alternative approaches may be preferred 1

ELF Limitations

• ELF is a patented test with limited availability and higher cost compared to FIB-4, restricting widespread application in clinical practice 1
• ELF has not been extensively tested in lean NAFLD patients, though it may be used as a confirmatory prognostic test until further data are available 1
• At low disease prevalence settings (primary care), ELF has limited positive predictive value at higher thresholds, requiring careful consideration of pre-test probability 5
• To achieve specificity of 0.90 for advanced fibrosis, an ELF threshold of 10.18 is required (sensitivity only 0.57), limiting diagnostic performance in low-prevalence populations 5

When to Escalate Testing Despite Low Scores

Clinical Red Flags Requiring Secondary Testing

• Consider transient elastography or ELF despite low FIB-4 if persistent ALT elevation >2× upper limit of normal (>40 U/L for women, >60 U/L for men) despite lifestyle modifications 2
• Consider secondary testing if clinical features suggest more advanced disease: splenomegaly, thrombocytopenia (<150,000/μL), or stigmata of chronic liver disease on examination 2
• Consider secondary testing if declining serum albumin below normal range in a patient with adequate nutrition 2
• Consider secondary testing in type 2 diabetes with poor glycemic control (HbA1c >8%) or multiple metabolic comorbidities despite reassuring FIB-4 2

When Specialist Referral Is Mandatory

• Hepatology referral is indicated when FIB-4 rises to ≥1.3 (or ≥2.0 if age ≥65) on repeat testing 2
• Hepatology referral is indicated when secondary testing shows high-risk results (transient elastography ≥12 kPa, ELF ≥9.8) 2
• Hepatology referral is mandatory if clinical decompensation develops (ascites, variceal bleeding, hepatic encephalopathy) regardless of noninvasive test results 2

Alternative and Complementary Testing Modalities

Transient Elastography (FibroScan)

• Transient elastography is the most widely available device for liver stiffness measurement with AUROC of 0.87 for advanced fibrosis and 0.92 for cirrhosis using M probe 1
• Liver stiffness measurement >8 kPa or ELF >9.5 has been used to prompt referral to secondary care liver services in existing pathways 1
• If ELF testing is unavailable or results are discordant with clinical suspicion, proceed directly to transient elastography or magnetic resonance elastography 2

Magnetic Resonance Elastography (MRE)

• MRE should be considered as a confirmatory test for fibrosis assessment when available, as it is less affected by BMI or body habitus compared to transient elastography 1
• MRE is more suited to clinical trials given its cost and limited availability, and is only marginally better than other noninvasive tests for F3-F4 fibrosis 1