The SAFE Score: A Superior Tool for Liver Disease Screening

Introduction

Chronic liver disease (CLD) is a significant global health issue, resulting in approximately 2 million deaths annually. Fibrosis in CLD marks a critical turning point, impacting prognosis. The primary causes of CLD are alcohol-related liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). Early detection of fibrosis allows for targeted interventions to curb progression and enhance survival. Efficient referral pathways are vital for managing these conditions.

Noninvasive Tests for Liver Fibrosis

While liver biopsy is the gold standard for assessing hepatitis and fibrosis, its invasiveness, sampling errors, and observer variations make it unfeasible for routine screening. Noninvasive tests (NITs) have transformed hepatology, reducing the need for liver biopsy. Transient elastography (TE) is the current standard for noninvasive liver fibrosis diagnosis, extensively validated for various CLD. However, TE is limited by availability, necessitating a blood-based tool for primary care.

The Steatosis-Associated Fibrosis Estimator (SAFE) Score

The SAFE score is a recent tool designed for primary care to estimate clinically significant liver fibrosis in NAFLD subjects. Unlike the enhanced Liver Fibrosis (ELF) test, SAFE utilizes readily available variables including age, body mass index (BMI), diabetes status, aminotransferase levels, globulin, and platelet count. It has been reported to outperform the Fibrosis-4 (FIB-4) and NAFLD fibrosis score (NFS) in identifying low-risk NAFLD patients and predicting survival.

Study Overview

This three-part study assessed the performance of FIB-4, NFS, and SAFE in screening the general population in the National Health and Nutrition Examination Surveys (NHANES) cohort (2017−2020) with TE as a fibrosis screening reference. In a separate large population-based study from an Asian center (2018−2020), we evaluated the diagnostic performance of these NITs in patients with various etiologies using liver biopsy as a reference. Finally, we applied the NITs on adults from the NHANES cohort (1999−2016) to study their correlation with mortality outcomes.

Participants and Methods

In part 1, we included 6,677 adults from the NHANES cohort (2017−2020). In part 2, we examined patients who underwent liver biopsies at an Asian center between 2018 and 2020. In part 3, we applied the SAFE score to adults in the NHANES cohort (1999−2016) to assess the correlation with mortality.

Performance of the NITs for Detecting Elevated Liver Stiffness

Using TE as a reference, SAFE outperformed FIB-4 in staging TE ≥8 kPa (AUC = 0.730 vs. 0.602, P < 0.01) and TE ≥12 kPa (AUC = 0.789 vs. 0.648, P < 0.01). SAFE was superior to NFS in staging TE ≥8 kPa (AUC = 0.730 vs. 0.707, P < 0.01), while it showed similar performance in staging TE ≥12 kPa (AUC = 0.789 vs. 0.766, P = 0.07).

Performance of the NITs Based on Validated Cutoffs in Staging TE Strata

Among the general population, SAFE (cutoff 100) had a lower proportion of false positives (10.4%) than FIB-4 (cutoff 1.30) (22.1%) and NFS (cutoff -1.455) (43.6%), while retaining a low proportion of missed patients with TE ≥8 kPa (5.5%). Among at-risk groups, SAFE (cutoff 100) spared more referrals (77.2%) than FIB-4, with a lower missed TE ≥8 kPa rate (54.4%) and similar missed TE ≥12 kPa rate (40.1%).

Performance of the NITs for Staging Fibrosis Stages Using Biopsy as Reference

In part 2, SAFE outperformed FIB-4 (P = 0.04) and NFS (P = 0.04) in staging significant fibrosis (≥S2) in NAFLD, while showing similar diagnostic accuracy to FIB-4 and NFS in other etiologies. The SAFE score was comparable to the FIB-4 and NFS for staging advanced fibrosis (≥S3).

Impact of the NITs on Mortality Outcome

In part 3, we included 46,357 adults for outcome assessment. The SAFE score predicted overall survival in the general population, with higher c-statistics than FIB-4 and NFS. Among the subgroup at risk for chronic liver disease, the high-risk group (SAFE >100) was independently associated with higher mortality, supported by non-overlapping confidence intervals with the other two strata.

Conclusions

Compared to the recommended FIB-4, using a SAFE-based referral pathway reduced futile referrals without raising the missed TE ≥8 kPa rate. Additionally, SAFE was more effective than FIB-4 and NFS in staging significant fibrosis in NAFLD individuals. Furthermore, SAFE is correlated with all-cause mortality in the general U.S. population, supporting its role as a primary care gatekeeper.

References

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