FIB-4, Forns Index May Aid Noninvasive Fibrosis Staging in Chronic HCV

Emmanuel Tsochatzis, MD, MSc, PhD

Credit: ResearchGate

The Fibrosis-4 (FIB-4) score and Forns index may be useful alternatives to liver biopsy for determining the presence and severity of fibrosis in chronic hepatitis C virus (HCV) infection, according to findings from a recent study.¹

Results suggest the FIB-4 score's low cut-off (1.45) can be used to rule out people with severe fibrosis (≥ F3) and cirrhosis (F4), while the Forns index's high cut-off (6.9) can be used to diagnose people with at least significant fibrosis (≥ F2).¹

Liver biopsy is commonly performed to help diagnose and stage various liver diseases, including metabolic dysfunction-associated steatotic liver disease, chronic HCV and HBV, and primary biliary cholangitis.² Prompt detection and treatment of fibrosis are essential for preventing progression to cirrhosis. Although liver biopsy is generally considered to be the “gold standard” for determining the stage and degree of liver damage, other non-invasive tests are available and may offer a viable alternative.³

“Liver biopsy is invasive, costly, painful, and carries some serious risks such as bleeding,” Emmanuel Tsochatzis, MD, MSc, PhD, a professor of hepatology and a consultant hepatologist at the UCL Institute for Liver and Digestive Health, and colleagues wrote.¹ “Accurately diagnosing liver fibrosis through non‐invasive tests such as the FIB‐4 score and Forns index would benefit people and healthcare systems overall. However, their diagnostic accuracy in people with hepatitis C infection remains unclear.”

To compare the diagnostic accuracy of FIB-4 and Forns index for staging liver fibrosis in people with chronic HCV, investigators used standard Cochrane search methods for diagnostic accuracy studies. Specifically, they included diagnostic cross-sectional or case-control studies that evaluated the performance of the FIB-4 score, the Forns index, or both, against liver biopsy, for assessing liver fibrosis in participants with chronic HCV. Studies in which participants had causes of liver disease besides chronic HCV; participants had successfully been treated for chronic HCV; or the interval between the index test and liver biopsy exceeded 6 months were excluded.¹

In total, investigators included 84 studies with a total of 107,583 participants. The studies were conducted in 28 countries and were published between 2002 and 2021. Of these studies, 82 (98%) were cross-sectional diagnostic accuracy studies with cohort-based sampling, and the remaining 2 (2%) were case-control studies.¹

Investigators performed meta-analyses using the bivariate model and calculated summary estimates. They evaluated the performance of both tests for 3 target conditions: significant fibrosis or worse (METAVIR stage ≥ F2); severe fibrosis or worse (METAVIR stage ≥ F3); and cirrhosis (METAVIR stage F4).¹

The meta-analysis was restricted to studies reporting cut-offs in a specified range (+/-0.15 for FIB-4; +/-0.3 for Forns index) around the original validated cut-offs (1.45 and 3.25 for FIB-4; 4.2 and 6.9 for Forns index). Based on these cut-offs, investigators analyzed results from 62 studies with 100,605 participants.¹

Investigators then calculated the percentage of people who would receive an indeterminate result, defined as a score above the rule-out threshold but below the rule-in threshold, for each index test/cut-off/target condition combination.¹

Of the 62 studies included in the main meta-analysis, 2 (2%) studies had low risk of bias, 23 (27%) studies had unclear risk of bias, and 59 (73%) studies had high risk of bias. Additionally, investigators judged 13 (15%) studies to have applicability concerns regarding participant selection.¹

The FIB-4 low cut-off (1.45) is designed to rule out people with at least severe fibrosis (≥ F3). Upon analysis, 39 study cohorts with 86,907 participants yielded a summary sensitivity of 81.1% (95% confidence interval [CI], 75.6%-85.6%), a specificity of 62.3% (95% CI, 57.4%-66.9%), and a negative likelihood ratio (LR-) of 0.30 (95% CI, 0.24-0.38).¹

The FIB-4 high cut-off (3.25) is designed to rule in people with at least severe fibrosis (≥ F3). Investigators noted 24 study cohorts with 81,350 participants yielded a summary sensitivity of 41.4% (95% CI, 33.0%-50.4%), a specificity of 92.6% (95% CI, 89.5%-94.9%), and a positive likelihood ratio (LR+) of 5.6 (95% CI, 4.4-7.1). Using the FIB-4 score to assess severe fibrosis and applying both cut-offs together, investigators determined 30.9% of people would obtain an indeterminate result requiring further investigation.¹

The Forns index low cut-off (4.2) is designed to rule out people with at least significant fibrosis (≥ F2). Upon analysis, 17 study cohorts with 4354 participants yielded a summary sensitivity of 84.7% (95% CI, 77.9%-89.7%), a specificity of 47.9% (95% CI, 38.6%-57.3%), and an LR- of 0.32 (95% CI, 0.25-0.41).¹

The Forns index high cut-off (6.9) is designed to rule in people with at least significant fibrosis (≥ F2). In total, 12 study cohorts with 3245 participants yielded a summary sensitivity of 34.1% (95% CI, 26.4%-42.8%), a specificity of 97.3% (95% CI, 92.9%-99.0%), and an LR+ of 12.5 (95% CI, 5.7-27.2). Using the Forns index to assess significant fibrosis and applying both cut-offs together, investigators determined 44.8% of people would obtain an indeterminate result requiring further investigation.¹

Of note, investigators deemed there were insufficient studies to meta-analyze the performance of the Forns index for diagnosing severe fibrosis and cirrhosis. Thus, comparisons of the 2 tests' performance were not possible for these target conditions.¹

However, for diagnosing significant fibrosis and worse, there were no significant differences in their performance when using the high cut-off. Investigators noted the Forns index performed slightly better than FIB-4 when using the low/rule-out cut-off (relative sensitivity, 1.12; 95% CI, 1.00-1.25; P = .0573; relative specificity, 0.69; 95% CI, 0.57-0.84; P = .002).¹

Investigators acknowledged multiple limitations to these findings, including the potential overestimation of diagnostic accuracy in some studies and notable variations in accuracy estimates across individual studies.¹

“Both the FIB‐4 score and Forns index can be used in the initial phase of investigating whether someone has liver scarring,” investigators concluded.¹ “It is best to use the FIB‐4 score to rule out stage 3 or stage 4 scarring. It is best to use the Forns index to diagnose people with stage 2 scarring.”

References

1. ^{Huttman M, Parigi TL, Zoncapè M, et al. Liver fibrosis stage based on the four factors (FIB‐4) score or Forns index in adults with chronic hepatitis C. Cochrane Database of Systematic Reviews 2024, Issue 8. doi:10.1002/14651858.CD011929.pub2.}
2. ^{Mayo Clinic. Liver biopsy. Tests & Procedures. January 5, 2023. Accessed September 5, 2024. https://www.mayoclinic.org/tests-procedures/liver-biopsy/about/pac-20394576}
3. ^{American Liver Foundation. Fibrosis (Scarring). About Your Liver. September 6, 2023. Accessed September 5, 2024. https://liverfoundation.org/about-your-liver/how-liver-diseases-progress/fibrosis-scarring/}