In this study, we validated the performance of the SAFE score in Asian patients with MASLD which were less obese than Western population. The SAFE score showed good performance for predicting significant fibrosis. This performance was consistent at both non-obese and obese patients with MASLD. The SAFE score outperformed the NFS and FIB-4 in predicting clinically significant fibrosis. Interestingly, the sensitivity and AUROC of the SAFE score tended to be younger in the younger group, which might require adjustment of cutoff value in this special age group. When we applied SAFE score to our liver biopsy cohort, the AUROC of the SAFE score was similar to those of the NFS and FIB-4 (0.790 vs. 0.800 vs. 0.802). These results suggest that SAFE score, which focused more on metabolic risk factors, might be utilized as a screening tool to identify high risk group in MASLD patients.
The AUROC of the SAFE score for predicting clinically significant fibrosis was 0.753, which was similar to the AUROC of the previous validation study.(23) Based on its predictive power > 0.7, the SAFE score is suitable for predicting significant fibrosis in Asian populations. The sensitivity of a SAFE score < 0 for predicting clinically significant fibrosis was 78.2%, which was lower than that of the previous study, which ranged from 90–98%.(15) However, the sensitivity for predicting significant fibrosis based on liver biopsy (89.7%) was similar to the previous data.(15) Since the original SAFE score was originated from biopsy results, this difference could be a result of discrepancies between diagnostic procedures. Despite the difference of study population, the sensitivity and specificity of SAFE scores < 0 and ≥ 100, the NPV of a SAFE score < 0, and the PPV of SAFE score ≥ 100 for predicting clinically significant fibrosis were similar to those reported previously in a validation study.(23)
In a recent study, SAFE score was validated with good performance in Asian patients with NAFLD.(24) In the territory-wide cohort from Hong Kong, 18.6%, 34.6% and 46.8% of patients were in the low-, intermediate- and high-risk groups, respectively. HK cohort included fewer low-risk patients and more high-risk patients. However, in our study, 47.1%, 31.1%, and 21.8% of patients were in the low-, intermediate- and high-risk groups. This reflects that the even Asian can have different at-risks of disease progression according to food, lifestyle, or metabolic risks. When we consider that SAFE score was developed to detect low-risk NAFLD, our cohort seems to be appropriate to validate this score. In addition, unlike previous studies, we focused on lean and non-obese patients, because original paper included patients who were mostly obese (BMI ≥ 30) and had few lean patients.(15) Asians have a higher proportion of MASLD with normal body weight compared with Westerners.(25) Among people with non-obese or lean NAFLD, 39.0% had steatohepatitis, 29.2% had significant fibrosis, and 3.2% had liver cirrhosis.(26) Additionally, lean patients with MASLD tend to have more severe liver disease and poorer outcomes compared with obese patients with MASLD.(27) Thus, it is important to validate the SAFE score in lean or non-obese patients, especially in Asian patients.
In our study, clinically significant fibrosis was more prevalent in obese patients compared to non-obese patients (25.9% vs. 13.4%). It is consistent with the previous report that lean NAFLD had less severe histologic findings than obese subjects.(26) The AUROC of SAFE score was slightly higher in lean or non-obese patients compared to overweight or obese patients. For predicting significant fibrosis based on TE, the AUROC was higher in females than males, whereas for predicting significant fibrosis based on biopsy results, the AUROC was higher in males than females, although statistically insignificant. These differences might be because in patients who received liver biopsy, males had less significant fibrosis stage compared to females. When we divided the patients according to age groups of 19–30, 31–40, 41–50, 51–60, 61 or more, sensitivity increased and specificity decreased by age. Because the SAFE score is used to assess the risk of significant fibrosis, the 16.1% sensitivity of a SAFE score cutoff ≥ 100 in patients 19–30 years of age is concerning. Moreover, the AUROC for predicting clinically significant fibrosis in the younger age groups was lower than that in the older age groups. Therefore, minor adjustments of parameters or cutoff values might be needed in younger patients. As in the previous validation study, patients with age of 19–40 had lower sensitivity (18.9%) compared to higher ages of 41–60 (49.0%) and 61 or more (79.7%).(23)
Primary risk assessment is important for identifying patients with MASLD who are at-risk for disease progression. The American Association for the Study of Liver Diseases (AASLD) and Europe Association for the Study of Liver Diseases (EASL) guidelines have recommended a two-step algorithm using FIB-4 and TE to identify patients at risk.(28, 29) FIB-4 has reasonable specificity but low sensitivity, and is mainly composed of liver-oriented variables.(30) Additionally, in patients with an indeterminate or high FIB-4, additional risk stratification using TE should be considered. Although TE is the best-validated imaging technique for fibrosis risk stratification, TE is not always available to use in a real clinical practice, especially for primary care physicians. Therefore, SAFE score can be used as a new and simple method which includes more metabolic variables such as BMI and DM. Metabolic dysfunction is closely associated with the development of MASLD. Therefore, with the shift from NAFLD to MASLD, SAFE score may have merits as a method to compensate the limitations of traditional non-invasive tests in MASLD patients. Additionally, the American Diabetic Association (ADA) also emphasized initial risk stratification of fibrosis and appropriate refer of at-risk patients with DM to a gastroenterologist or hepatologist for further workup.(31) The SAFE score is expected to be the primary tool for risk stratification of patients with MASLD and/or DM, where metabolic risk is being increasingly important.
This study has several limitations. First, this is retrospective data from single tertiary center. However, most of MASLD patients referred from health check-up or primary care physician. Thus, this cohort is suitable for validating SAFE score to detect low-risk MASLD patients. Second, all patients were consisted of Korean. However, it is significant in that is it the first study to validate the performance of SAFE score in different ethnicity, which includes large portion of lean or non-obese population. Third, BMI, DM, and age are components of the SAFE score, possibly resulting in overfitting if the values were fitted to the individual subgroups. Additionally, we used subgroups to validate the performance of the SAFE score, rather than for fitting the model. We focused on demonstrating that the SAFE score has non-inferior performance in non-obese patients. Second, 492 patients had biopsy results, resulting in wide confidence intervals. However, because TE has been validated as a non-invasive test for predicting fibrosis,(14, 32) and not all MASLD patients undergo liver biopsy, the results of this study have clinical relevance.
In conclusion, we externally validated good performance of SAFE score in Asian patients. The SAFE score has potential as an initial assessment to identify low-risk population in a primary care setting. Further studies are needed to validate the use of SAFE score with long-term follow-up.