A total of 576 subjects were included in this analysis. Of these, 280 (49%) were women and 418 (73%) were obese (Table ); 241 (42%) had type 2 DM and 184 (32%) were hypertensive. A total of 319 subjects had steatohepatitis, of whom 64 subjects had advanced fibrosis. As expected, subjects with more advanced fibrosis were significantly older, predominantly female, and more likely to be hypertensive, to have type 2 DM, to have higher AST, AAR, GGT, FPG, and IRI, and to have lower hemoglobin, platelet count, albumin, ChE, total cholesterol, and triglyceride. Regarding the individual components of the FIB4 score, the mean (± SD) or median [interquartile range] values were as follows: age (52.3 ± 15.4 years); AST (43 [30-67] IU/L); ALT (69 [43-112] IU/L), and platelets (227 ± 67 × 109/L) (Table ). The distribution of fibrosis stages included stage 0 (n = 263), stage 1 (n = 169), stage 2 (n = 80), stage 3 (n = 45), and stage 4 (n = 19). FIB4 values for the whole sample ranged from 0.17-10.74. The median FIB4 score was 1.23 (interquartile range, 0.77-2.02) (Table ). The mean (interquartile range) FIB4 indices for stages 0, 1, 2, 3, and 4 were 1.09 (0.61-1.34), 1.40 (0.77-1.88), 2.36 (1.44-3.15), 3.23 (1.82-4.04), and 4.48 (3.19-5.17), respectively (p < 0.0001 by analysis of variance). The mean (interquartile range) FIB4 index was 1.13 (0.71-1.79) in patients with stage 0-2 fibrosis and 3.17 (1.88-4.25) in patients with stage 3-4 fibrosis (p <0.0001) (Table ).
The sensitivity and specificity of FIB4 along the ROC were assessed first. At a sensitivity of 90% (FIB4 = 1.45) the specificity was 35%, while at a specificity of 90% (FIB4 = 2.67), the sensitivity was 52%. ROC curves were then developed for each of the noninvasive marker panels and superimposed, to determine which score would have the most clinical utility (Figure ). ROC curves were created to determine the utility of the indices for predicting advanced fibrosis (stage 3 and 4 versus lower scores). The AUROC was greatest for FIB4 (0.871), followed by NFS (0.863), APRI (0.823), AP index (0.810), AAR (0.788), BARD score (0.765), and N score (0.715) (Table ). As the NPVs for FIB4 index, AAR, APRI, AP index, NFS, BARD score, and N score were all greater than 95% using their lower cut-offs, these tests may have sufficient accuracy to be used clinically to exclude advanced fibrosis. Using this approach, a significant proportion of patients could avoid liver biopsy using each of these tests (Table ). As the PPV were modest for all noninvasive tests, ranging from 19% to 53%, it was felt they were not accurate enough to be used as an alternative to liver biopsy. The PPV for FIB4 is highest among other noninvasive tests.
Using the low cut-off point proposed by Sterling and colleagues (< 1.45)[22
], 330 of 336 (98.3%) patients without stage 3 or 4 fibrosis were correctly staged, while only 6 (1.7%) were under-staged (Table ). All of the 6 patients with advanced fibrosis but FIB4 index below the low cut-off point had stage 3 fibrosis, none had stage 4 fibrosis. The NPV of this cut-off for stage 3 or 4 fibrosis was 98%. Using the high cut-off point proposed by Sterling and colleagues (> 3.25) [24
], 31 of 59 (52.5%) patients with stage 3 or 4 fibrosis were correctly staged, while 28 (47.5%) were over-staged. Among the 28 patients without advanced fibrosis but FIB4 index above the high cut-off point, 18 had stage 2 fibrosis, 6 had stage 1, and 4 had no fibrosis. The PPV of this cut-off for stage 3 or 4 fibrosis was 53%. A total of 395 patients (69% of the cohort) had a FIB4 index < 1.45 or > 3.25; FIB4 identified the absence or presence of advanced fibrosis with 91% accuracy in these 361 subjects. A total of 181 subjects (31%) had FIB4 values in the indeterminate range (1.4-3.25).
Proportion of patients who may potentially avoid liver biopsy using the simple non-invasive tests to exclude advanced fibrosis.
On the other hand, using the low cut-off point proposed by Shah and colleagues (< 1.30) [24
], 304 of 308 (99%) patients without stage 3 or 4 fibrosis were correctly staged, while only 4 (1%) were under-staged (Table ). All of the 4 patients with advanced fibrosis but FIB4 index below the low cut-off point had stage 3 fibrosis and none had stage 4 fibrosis. The NPV of this cut-off for stage 3 or 4 fibrosis was 99%. Using the high cut-off point proposed by Shah and colleagues (> 2.67), 38 of 89 (43%) patients with stage 3 or 4 fibrosis were correctly staged, while 51 (57%) were over-staged. Among the 51 patients without advanced fibrosis but NAFLD fibrosis scores above the high cut-off point, 28 had stage 2 fibrosis, 14 had stage 1, and 9 had no fibrosis. The PPV of this cut-off for stage 3 or 4 fibrosis was 43%. A total of 397 patients (69% of the cohort) had a FIB4 index < 1.30 or > 2.67; FIB4 identified the absence or presence of advanced fibrosis with 86% accuracy in these 342 subjects. A total of 179 subjects (31%) had FIB4 values in the indeterminate range (1.30-2.67). Thus the prevalence of patients in the indeterminate range was similar using the two different cut-off values, but the number of patients with true positive or true negative predictions (accuracy) was higher using Sterling et al
.'s cut-off values compared with Shah et al
.'s (361 patients versus 342 patients). If liver biopsies were only performed in patients with an FIB4 index above the low cut-off point (> 1.45) proposed by Sterling, 336 (58%) of 576 biopsies could be avoided (Table ).
The diagnostic accuracy of FIB4 index for detecting advanced fibrosis (stage 3-4) was also compared to that of NFS (Table ). Three hundred and seventy patients (64% of the cohort) had an NFS <-1.455 or > 0.676; NFS identified the absence or presence of advanced fibrosis with 93% accuracy in these 344 subjects. A total of 206 subjects (36%) had NFS values in the indeterminate range (-1.455-0.676). Although the accuracy of NFS was higher (93%) than that of FIB4 (86%), more patients were correctly staged with FIB4 (n = 361) than with NFS (n = 344). Moreover, the percentage of patients in the undetermined range was lower for the FIB4 index (31%) than for NFS (36%). Using the cut-off values reported by Sterling and colleagues, discrepancies between FIB4 index and NFS were observed in 146 (39%) patients (Table ). Patients were categorized into three groups, "low-risk" (< 10%), "intermediate-risk" (10-30%) and "high-risk" (> 30%), based on the combination of FIB4 index and NFS (Table ). Only 1 patient (0.4%) of 243 patients with the low cut-off points for both FIB4 index and NFS had advanced fibrosis.
Categorized risk groups for advanced fibrosis according to combined FIB4 index and NAFLD fibrosis score (NFS).