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Ballestri et al. Metab Target Organ Damage 2023;3:1     https://dx.doi.org/10.20517/mtod.2022.23                                                                               Page 5 of 22



                          Table 1. Indirect biomarkers of liver fibrosis

                                               Author                                                                                                                                            Cut-offs    AUROC
                          Biomarker                       Equation
                                               (ref.)                                                                                                                                            for F3/F4 *
                          AST: ALT ratio (AAR) Williams   AST (IU/L)/ALT (IU/l)                                                                                                                  < 0.8 to rule  -
                                                   [36]
                                               et al.                                                                                                                                            out
                                                                                                                                                                                                 > 1.0 to rule
                                                                                                                                                                                                 in**
                                                                                       9
                          Forns index          Forns      7.811-3.131 ln [platelet count (×10 /L)] + 0.781 ln [GGT (IU/L)] + 3.467 ln [age (years)]-0.014 [cholesterol (mg/dl)]                  < 4.2 to rule  0.81
                                                   [37]
                                               et al.                                                                                                                                            out
                                                                                                                                                                                                 > 6.9 to rule
                                                                                                                                                                                                  ¶
                                                                                                                                                                                                 in
                                                                                            9
                          AST-to-platelet ratio  Wai      AST (IU/L)/(ULN)/platelet count (×10 /L) × 100                                                                                         ≤ 0.5 to rule  0.88
                                                   [38]
                          index (APRI) score   et al.                                                                                                                                            out
                                                                                                                                                                                                 > 1.5 to rule
                                                                                                                                                                                                  ¶
                                                                                                                                                                                                 in
                                                                                       2
                          BARD score           Harrison   Weighted sum of BMI ≥ 28 kg/m , 1 point                                                                                                ≥ 2 points to  0.81
                                                   [39]
                                               et al.     AST/ALT ratio ≥ 0.8, 2 points                                                                                                          rule in
                                                          Diabetes present, 1 point
                                                                                            9
                          Fibrosis-4 index (FIB- Sterling   Age × AST (IU/L)/platelet count (×10 /L) × √ALT (IU/l)                                                                               < 1.45 to   0.765
                                                   [40]
                          4)                   et al.                                                                                                                                            rule out
                                                                                                                                                                                                 > 3.25 to
                                                                                                                                                                                                 rule in
                                                                                                       2                                                                                  9
                          NAFLD fibrosis score  Angulo    -1.675 + 0.037 × age (years) + 0.094 × BMI (Kg/m ) + 1.13 × IFG or T2D (yes = 1; no = 0 =) + 0.99 × AST/ALT ratio - 0.013 × platelet count (×10 /L)-  < -1.45 (<   0.82
                                                   [41]
                          (NFS)                et al.     0.66 × albumin (g/dL)                                                                                                                  65 years)
                                                                                                                                                                                                 < 0.12 (> 65
                                                                                                                                                                                                 years) to
                                                                                                                                                                                                 rule out^
                                                                                                                                                                                                 ≥ 0.67 to
                                                                                                                                                                                                 rule in
                                                                                           9
                          GGT-to-platelet ratio  Lemoine   GGT/ULN of GGT/platelet count (10 /L) ×100                                                                                            > 0.32 to   0.76-
                                                   [43]
                          (GPR)                et al.                                                                                                                                            rule in     0.93°
                          Hepamet fibrosis     Ampuero  1/[1 + e (5.390-0.986 (if Age 45-64 years) - 1.719 (if Age ≥ 65 years) + 0.875 (if Male sex) - 0.896 (if AST 35-69 IU/L) - 2.126 (if AST ≥ 70 IU/L) -   < 0.12 to   0.84
                                                   [44]
                          score (HFS)          et al.     0.027 (if Albumin 4-4.49 g/dL) - 0.897 (if Albumin < 4 g/dL) - 0.899 (if HOMA 2-3.99 with no DM) -1.497 (if HOMA ≥ 4 with no DM) - 2.184 (if DM)  rule out
                                                          - 0.882 (if Platelets 155-219 × 1000/µL) - 2.233 (if Platelets < 155 × 1000/µL))]                                                      > 0.47 to
                                                                                                                                                                                                 rule in


                          AUROC: Area under the receiver operating characteristics; AST: aspartate aminotransferase; ALT: alanine aminotransferase; BMI: body mass index; DM: diabetes mellitus; IFG impaired fasting glucose; HOMA:
                          homeostasis model assessment; IU: international units; GGT: gamma-glutamyl transpeptidase; T2D: type 2 diabetes; ULN: upper limit of normal; -: not available; *AUROC values for validation sets; **Original cut-off
                                                   ¶                                                                                                 [42]
                          developed for cirrhosis (F4);  Original cut-off developed for significant fibrosis (F2 to F4); ^age-related cut-off, according to McPherson et al.  ; °two validation cohorts.


                          markers (NFS; FIB4; Fibrotest; FibroMeter), vibration-controlled transient elastography (VCTE), and the combinatory elasto-blood test FibroMeterVCTE. The

                          authors found that the AUROCs were significantly lower among type 2 diabetes (T2D) patients, mainly owing to decreased specificity. The reasons underlying
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