Assessing Strategies to Mitigate the Effect of Age When Using FIB-4 Index to Screen for MASLD-Related Liver Fibrosis

Fibrosis-4 (FIB-4) is recommended to screen for liver fibrosis in at-risk individuals, but its performance is limited at extremes of age. This study compared different strategies to limit the effect of age on FIB-4.

Using 2 independent MASLD cohorts, we assessed FIB-4 and four alternative strategies to detect ≥F2, ≥F3, and cirrhosis. The strategies assessed were: (1) standard FIB-4 with 1.3 as cutoff; (2) FIB-4, but using a cutoff of 2.0 for ≥65 years; (3) FIB-3 where age was removed from FIB-4 formula; (4) capped FIB-4 (where 35 or 65 were used as age inputs in individuals <35 or >65, respectively), and (5) log-transformed FIB-4, where natural logarithm of age was used. Magnetic resonance elastography (MRE) was used as reference in cohort #1 (n=604), and liver biopsy in cohort #2 (n=334). NHANES 2017-2020 was used to assess the strategies in an unselected cohort.

Among 938 participants (54±12 years, 50% female, 34.7±6.7 kg/m², 42% with diabetes), 20% had ≥F2, 13% ≥F3, and 3% cirrhosis. All strategies had similar AUROCs for detection of ≥F2 or ≥F3 versus MRE (AUROCs 0.76-0.78) or liver biopsy (AUROCs 0.77-0.81). Based on prespecified or calculated cut-off points, strategies differed in sensitivity and specificity, but without major impact on PPV and NPV. FIB-3 demonstrated a balanced sensitivity-specificity trade-off at age extremes (<35-year-old and ≥65-year-old individuals).

In adults with MASLD, strategies to limit age effect on FIB-4 maintained discrimination relative to standard FIB-4. An age-independent approach (FIB-3) maintains diagnostic accuracy across diverse age strata, supporting further prospective evaluation in primary-care screening populations.