Study Describes Fibrosis Risk Misclassification with FIB-4 Compared to Transient Elastography

Mazen Noureddin, MD, MHSc

Credit: Houston Methodist

Findings from a recent study suggest clinicians should use caution when interpreting Fibrosis-4 index (FIB-4) scores to risk-stratify patients for metabolic dysfunction-associated steatotic liver disease (MASLD)-related fibrosis.¹

Applying American Gastroenterological Association (AGA)/American Association for the Study of Liver Diseases (AASLD) guidelines for FIB-4 to a general population of 2017- 2020 National Health and Nutrition Examination Survey (NHANES) participants, the study found substantial misclassification with FIB-4 compared to liver stiffness measurement (LSM) obtained through FibroScan vibration-controlled transient elastography (VCTE).¹

Although liver biopsy is generally considered to be the “gold standard” for diagnosing MASLD and assessing fibrosis, notable limitations to its use include cost, sampling error, and potential procedure-related complications. Noninvasive diagnostic tests are often used as an alternative, with the 2021 AGA Clinical Care Pathway and 2023 AASLD Practice Guidance for screening patients for advanced fibrosis recommending sequential testing with FIB-4, followed by FibroScan for patients classified as having indeterminate risk by FIB-4.^2,3

“Previous studies have shown FIB-4 to have low accuracy for screening liver fibrosis, especially among obese and diabetic patients,” Mazen Noureddin, MD, MHSc, medical director of the Houston Research Institute and professor of medicine at Houston Methodist Academic Institute, and colleagues wrote.¹ “Thus, there is a concern that classifying patients with FIB-4 can lead to misclassification and missed diagnosis.”

To assess the performance and accuracy of FIB-4 for MASLD-related fibrosis risk stratification, investigators examined FibroScan data for NHANES 2017-2020 participants ≥ 18 years of age and followed AGA/AASLD guidelines for fibrosis risk identification. After identifying subjects at risk for clinically significant fibrosis, investigators eliminated those with chronic hepatitis C virus infection or chronic hepatitis B virus infection, as well as subjects without the FIB-4 variables of age, ALT, AST, and platelet count. They then divided participants into low-, indeterminate-, and high-risk groups based on the following FIB-4 cutoffs: <1.3 for low risk, >2.67 for high risk, and 1.3-2.67 for indeterminate risk.¹

In total, 5285 eligible NHANES participants were identified. Following the recommended AGA/AASLD pathways, investigators first identified subjects at risk for clinically significant fibrosis, leaving them with 3741 (70.8%) participants. Of these, 2776 (74.2%) were classified as low risk by FIB-4, and 86 (2.3%) were classified as high risk by FIB-4.¹

Of the 2776 patients classified as low risk for advanced liver fibrosis based on FIB-4, 277 (10%) were not low risk based on FibroScan because they had a LSM ≥8 kPa. Investigators pointed out 75 (2.7%) of these participants classified as low-risk based on FIB-4 were considered high-risk by FibroScan, with an LSM >12 kPa.¹

A total of 879 (23.5%) participants were classified as indeterminate by FIB-4. Among the 879 indeterminate patients, 777 (88.4%) were classified as low risk, 65 (7.4%) were classified as indeterminate risk, and 37 (4.2%) were classified as high risk by FibroScan. Additionally, investigators noted of the 86 patients classified as high risk based on FIB-4 cutoff, 68 (79.1%) were not high-risk based on FibroScan, and 62.8% were considered low risk (LSM <8 kPa).¹

Upon closer inspection of participants who were misclassified as low risk by FIB-4, investigators noted these patients had a significantly greater average age (46.86 vs 43.87 years); body mass index (39.33 vs 31.27 kg/m2); waist circumference (120.60 vs 103.63 cm); HbA1c level (6.41% vs 5.88%); ALT (32.61 vs 24.28 U/L); AST (24.14 vs 20.52 U/L); diastolic blood pressure (79.53 vs 77.08 mmHg); CAP score (324.99 vs 275.24 dB/m); white blood cell count (8.20 vs 7.48 × 109/L); alkaline phosphatase (85.98 vs 78.54 IU/L); and fasting glucose (132.67 vs 121.06 mg/dL). Additionally, they had lower high-density lipoprotein levels (44.51 vs 49.25 mg/dL) and albumin levels (3.98 vs 4.07 g/dL), and were also more likely to have prediabetes/diabetes (69.3% vs 49.6%).¹

Multivariable logistic regression analysis revealed being misclassified as low risk by FIB-4 was significantly associated with increased age (adjusted odds ratio [aOR], 1.02; 95% CI, 1.00-1.03), BMI (aOR, 1.11; 95% CI, 1.07-1.14), and CAP score (aOR, 1.01; 95% CI, 1.01-1.01).¹

“We discovered that there are a significant number of subjects who were misclassified by the pathway as low risk when they were in fact high risk for advanced fibrosis based on LSM,” investigators concluded.¹ “We also identified the characteristics of the subjects who were prone to being misclassified by FIB-4 as low risk. Based on these findings, we recommend an exercise of caution when interpreting low-risk FIB-4 results in patients with characteristics that confer a higher likelihood of being misclassified.”

References

1. ^{Chang M, Chang D, Kodali S, et al. Degree of Discordance Between FIB-4 and Transient Elastography: An Application of Current Guidelines on General Population Cohort. Clin Gastroenterol Hepatol. 2024;22(7):1453-1461.e2. doi:10.1016/j.cgh.2024.02.008}
2. ^{Kanwal F, Shubrook JH, Adams LA, et al. Clinical Care Pathway for the Risk Stratification and Management of Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology. https://doi.org/10.1053/j.gastro.2021.07.049}
3. ^{Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023;77(5):1797-1835. doi:10.1097/HEP.0000000000000323}