Noninvasive Models to Assess Liver Inflammation and Fibrosis in Chronic HBV Infected Patients with Normal or Mildly Elevated Alanine Transaminase Levels: Which One Is Most Suitable?
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patients
2.2. Liver Histological Examination
2.3. Noninvasive Models
2.4. Statistical Analysis
3. Results
3.1. Patient Characteristics
3.2. Validation of Noninvasive Models in All Patients
3.3. Evaluation and Comparison of Noninvasive Models in the HBeAg-Negative and HBeAg-Positive Groups
3.4. Reassessment and Comparison of Noninvasive Models in Patients with Varying Levels of ALT below Two Times the ULN (ULN = 40 U/L)
3.5. Evaluation and Comparison of Noninvasive Models Developed in Cohorts with CHB versus Those in Other Chronic Liver Diseases (CLDs)
3.6. Comprehensive Evaluation of Noninvasive Models
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
References
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Histology Stages | Points | |||
---|---|---|---|---|
0 | 1 | 2 | 3 | |
S ≥ 2 or G ≥ 2 | <0.70 | 0.70–0.75 | 0.75–0.80 | ≥0.80 |
S ≥ 3 or G ≥ 3 | <0.70 | 0.70–0.75 | 0.75–0.80 | ≥0.80 |
Variables | Total (n = 599) | S0–1 (n = 411) | S2–4 (n = 188) | p-Value (S0–1 vs. S2–4) |
---|---|---|---|---|
Age, years # | 37(31, 43) | 36(31, 43) | 37(32, 43) | 0.357 |
Male, n (%) | 411(68.6) | 269(65.5) | 142(75.5) | 0.014 * |
Log10[HBsAg], IU/mL # | 3.36(2.88, 3.86) | 3.32(2.86, 3.91) | 3.43(3.0, 3.81) | 0.656 |
HBeAg positive, n (%) | 221(35.2%) | 150(36.5%) | 71(37.8%) | 0.781 |
Log10[HBVDNA], IU/mL # | 4.67(3.38, 6.81) | 4.425(3.2975, 7.8025) | 5.16(3.675, 6.11) | 0.773 |
CP (mg/dL) # | 0.201 ± 0.039 | 0.204 ± 0.037 | 0.197 ± 0.043 | 0.143 |
AFP (ng/mL) # | 2.58(1.8, 4.0) | 2.29(1.74, 3.50) | 3.28(1.98, 5.98) | 0.000 * |
PT (s) # | 13.3(12.9, 13.9) | 13.2(12.8, 13.675) | 13.55(13.1, 14.1) | 0.000 * |
PTA (%) & | 97.8 ± 12.1 | 99.5 ± 12.4 | 94.0 ± 10.9 | 0.000 * |
INR # | 1.01(0.97, 1.06) | 1.01(0.96, 1.05) | 1.04(1.01, 1.09) | 0.000 * |
AST (U/L) # | 26(21, 31) | 24(21, 29) | 28(24, 35) | 0.000 * |
ALT (U/L) # | 31(22, 41) | 28(21, 40) | 36(25, 43.75) | 0.001 * |
GGT (U/L) # | 22(16, 32) | 20(15, 29) | 28(19,38.75) | 0.000 * |
ALP (U/L) # | 63(53, 76) | 62(52, 73) | 66.5(55, 83.25) | 0.001 * |
TBA (µmol/L) # | 4.3(2.4, 8.6) | 3.6(2.1, 7.7) | 5.8(3.55, 12.55) | 0.000 * |
CHE (U/L) # | 8616 ± 2047 | 8833 ± 2079 | 8135 ± 1893 | 0.000 * |
Glu (mmol/L) # | 5.04(4.64, 5.525) | 5.04(4.65, 5.49) | 5.02(4.6125, 5.49) | 0.848 |
TCHO (mmol/L) # | 4.81(4.3, 5.48) | 4.85(4.32, 5.45) | 4.77(4.22, 5.58) | 0.743 |
ApoA1 (g/L) # | 1.3(1.2, 1.5) | 1.3(1.2, 1.5) | 1.4(1.2, 1.5) | 0.020 * |
TBIL (µmol/L) # | 10.3(7.5, 14.35) | 10.1(7.2325, 14.675) | 11(8.25, 13.8) | 0.172 |
DBIL (µmol/L) # | 2.8(1.9, 4.2) | 2.6(1.8, 4.1) | 3.2(2.3, 4.3) | 0.001 * |
ALB (g/L) & | 46.1 ± 3.5 | 46.5 ± 3.2 | 45.3 ± 4.0 | 0.000 * |
GLO (g/L) & | 27.5 ± 3.8 | 27.2 ± 3.6 | 28.0 ± 4.0 | 0.01 * |
PLT (×109/L) # | 216(184, 250) | 222(192, 258) | 198(163, 231) | 0.000 * |
N (×109/L) # | 3.25(2.59, 4.18) | 3.36(2.64, 4.29) | 3.115(2.4725, 3.9225) | 0.035 * |
L (×109/L) # | 1.74(1.45, 2.12) | 1.74(1.44, 2.09) | 1.75(1.4725, 2.175) | 0.364 |
RDW-SD (fl) # | 40.2(38.4, 42.4) | 40(38.3, 42.0) | 40.75(38.525, 43.175) | 0.015 * |
Noninvasive Models | Significant Fibrosis (S ≥ 2) | Advanced Fibrosis (S ≥ 3) | Significant Inflammation G ≥ 2 | Advanced Inflammation G ≥ 3 | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Total (n = 188) | HBeAg (+) (n = 71) | HBeAg (−) (n = 117) | Total (n = 64) | HBeAg (+) (n = 27) | HBeAg (−) (n = 37) | Total (n = 191) | HBeAg (+) (n = 80) | HBeAg (−) (n = 110) | Total (n = 50) | HBeAg (+) (n = 21) | HBeAg (−) (n = 29) | |
AA index | 0.600 | 0.559 | 0.621 | 0.684 | 0.681 | 0.684 | 0.630 | 0.573 | 0.662 | 0.673 | 0.662 | 0.677 |
AAR | 0.533 | 0.581 | 0.505 | 0.594 | 0.689 | 0.529 | 0.488 | 0.517 | 0.479 | 0.597 | 0.697 | 0.529 |
AARPRI | 0.616 | 0.644 | 0.599 | 0.687 | 0.752 | 0.643 | 0.577 | 0.592 | 0.581 | 0.710 | 0.753 | 0.682 |
ABA | 0.570 | 0.607 | 0.549 | 0.651 | 0.696 | 0.636 | 0.596 | 0.634 | 0.594 | 0.689 | 0.692 | 0.709 |
AGAP | 0.713 | 0.750 | 0.695 | 0.794 | 0.823 | 0.784 | 0.733 | 0.754 | 0.736 | 0.857 | 0.841 | 0.881 |
AGPR | 0.698 | 0.710 | 0.691 | 0.768 | 0.812 | 0.743 | 0.701 | 0.724 | 0.696 | 0.812 | 0.801 | 0.827 |
ALRI | 0.590 | 0.553 | 0.607 | 0.652 | 0.634 | 0.658 | 0.606 | 0.597 | 0.606 | 0.691 | 0.629 | 0.730 |
APGA | 0.750 | 0.761 | 0.745 | 0.832 | 0.846 | 0.824 | 0.779 | 0.781 | 0.785 | 0.874 | 0.878 | 0.873 |
AP index | 0.627 | 0.687 | 0.594 | 0.666 | 0.724 | 0.645 | 0.636 | 0.694 | 0.626 | 0.695 | 0.703 | 0.714 |
APRI | 0.692 | 0.690 | 0.689 | 0.760 | 0.731 | 0.772 | 0.720 | 0.711 | 0.722 | 0.826 | 0.772 | 0.857 |
APPCI | 0.726 | 0.682 | 0.757 | 0.786 | 0.806 | 0.777 | 0.720 | 0.717 | 0.725 | 0.737 | 0.737 | 0.736 |
APPR | 0.670 | 0.668 | 0.674 | 0.721 | 0.773 | 0.692 | 0.673 | 0.690 | 0.670 | 0.761 | 0.741 | 0.784 |
APRG | 0.686 | 0.701 | 0.678 | 0.788 | 0.812 | 0.776 | 0.713 | 0.729 | 0.714 | 0.836 | 0.811 | 0.863 |
ATPI model | 0.649 | 0.628 | 0.658 | 0.737 | 0.740 | 0.732 | 0.650 | 0.655 | 0.646 | 0.771 | 0.742 | 0.788 |
CDS | 0.634 | 0.649 | 0.625 | 0.707 | 0.749 | 0.678 | 0.613 | 0.615 | 0.617 | 0.716 | 0.759 | 0.687 |
Doha score | 0.656 | 0.684 | 0.642 | 0.730 | 0.749 | 0.722 | 0.672 | 0.679 | 0.677 | 0.760 | 0.748 | 0.773 |
eLIFT | 0.676 | 0.714 | 0.655 | 0.749 | 0.811 | 0.713 | 0.688 | 0.716 | 0.691 | 0.783 | 0.800 | 0.780 |
FCI | 0.670 | 0.643 | 0.684 | 0.736 | 0.743 | 0.730 | 0.652 | 0.658 | 0.652 | 0.747 | 0.699 | 0.781 |
FI | 0.662 | 0.677 | 0.650 | 0.761 | 0.758 | 0.763 | 0.694 | 0.670 | 0.716 | 0.821 | 0.795 | 0.839 |
FIB-4 | 0.659 | 0.717 | 0.630 | 0.726 | 0.790 | 0.698 | 0.672 | 0.719 | 0.671 | 0.769 | 0.797 | 0.769 |
mFIB-4 | 0.610 | 0.677 | 0.572 | 0.675 | 0.771 | 0.616 | 0.595 | 0.650 | 0.585 | 0.691 | 0.765 | 0.650 |
FIB-5 | 0.368 | 0.390 | 0.355 | 0.332 | 0.409 | 0.276 | 0.326 | 0.361 | 0.300 | 0.279 | 0.394 | 0.196 |
FIB-6 | 0.647 | 0.689 | 0.627 | 0.737 | 0.779 | 0.727 | 0.700 | 0.725 | 0.709 | 0.823 | 0.803 | 0.866 |
FibroQ | 0.623 | 0.687 | 0.588 | 0.692 | 0.789 | 0.634 | 0.604 | 0.657 | 0.597 | 0.701 | 0.777 | 0.662 |
Forns | 0.643 | 0.713 | 0.615 | 0.729 | 0.805 | 0.715 | 0.639 | 0.707 | 0.638 | 0.743 | 0.755 | 0.799 |
Fibro-α | 0.674 | 0.696 | 0.665 | 0.746 | 0.818 | 0.705 | 0.649 | 0.670 | 0.654 | 0.773 | 0.854 | 0.720 |
GAPI | 0.719 | 0.756 | 0.701 | 0.802 | 0.859 | 0.772 | 0.705 | 0.725 | 0.708 | 0.834 | 0.850 | 0.836 |
Gao-2 | 0.637 | 0.703 | 0.643 | 0.689 | 0.752 | 0.729 | 0.652 | 0.700 | 0.672 | 0.741 | 0.771 | 0.787 |
Gao-1 | 0.677 | 0.770 | 0.619 | 0.750 | 0.851 | 0.675 | 0.689 | 0.794 | 0.662 | 0.793 | 0.873 | 0.750 |
GqHBsR | 0.650 | 0.695 | 0.633 | 0.684 | 0.774 | 0.643 | 0.632 | 0.653 | 0.634 | 0.728 | 0.784 | 0.707 |
GP | 0.651 | 0.673 | 0.637 | 0.738 | 0.745 | 0.737 | 0.671 | 0.682 | 0.671 | 0.787 | 0.787 | 0.788 |
GPR | 0.698 | 0.731 | 0.684 | 0.773 | 0.817 | 0.753 | 0.695 | 0.697 | 0.705 | 0.818 | 0.835 | 0.817 |
GUCI | 0.706 | 0.700 | 0.706 | 0.777 | 0.750 | 0.787 | 0.720 | 0.712 | 0.719 | 0.832 | 0.782 | 0.857 |
HBeAg(+)model | 0.637 | 0.703 | 0.619 | 0.689 | 0.752 | 0.675 | 0.652 | 0.700 | 0.662 | 0.741 | 0.771 | 0.750 |
HB-F | 0.659 | 0.686 | 0.641 | 0.743 | 0.815 | 0.693 | 0.648 | 0.662 | 0.650 | 0.738 | 0.790 | 0.704 |
HGM-1 | 0.643 | 0.619 | 0.660 | 0.732 | 0.735 | 0.738 | 0.659 | 0.638 | 0.680 | 0.784 | 0.746 | 0.823 |
HGM-2 | 0.443 | 0.416 | 0.457 | 0.431 | 0.418 | 0.425 | 0.429 | 0.399 | 0.432 | 0.391 | 0.416 | 0.356 |
IT model | 0.570 | 0.638 | 0.549 | 0.577 | 0.676 | 0.537 | 0.542 | 0.628 | 0.522 | 0.569 | 0.657 | 0.539 |
INPR | 0.667 | 0.689 | 0.656 | 0.734 | 0.758 | 0.721 | 0.659 | 0.682 | 0.653 | 0.738 | 0.741 | 0.740 |
King’s score | 0.690 | 0.718 | 0.677 | 0.754 | 0.767 | 0.754 | 0.719 | 0.747 | 0.714 | 0.807 | 0.773 | 0.839 |
Lok index | 0.664 | 0.673 | 0.656 | 0.745 | 0.796 | 0.707 | 0.640 | 0.634 | 0.649 | 0.739 | 0.771 | 0.715 |
Logit(Y) | 0.691 | 0.661 | 0.703 | 0.751 | 0.708 | 0.773 | 0.725 | 0.687 | 0.744 | 0.833 | 0.758 | 0.879 |
Mehdi’s model | 0.592 | 0.370 | 0.718 | 0.619 | 0.350 | 0.751 | 0.646 | 0.417 | 0.783 | 0.680 | 0.376 | 0.858 |
NLR | 0.453 | 0.427 | 0.469 | 0.496 | 0.499 | 0.499 | 0.426 | 0.455 | 0.408 | 0.449 | 0.399 | 0.488 |
NIKEI | 0.566 | 0.636 | 0.526 | 0.629 | 0.740 | 0.567 | 0.557 | 0.634 | 0.539 | 0.648 | 0.751 | 0.596 |
PAPAS | 0.639 | 0.697 | 0.616 | 0.670 | 0.731 | 0.653 | 0.675 | 0.746 | 0.674 | 0.700 | 0.731 | 0.704 |
PGA | 0.542 | 0.553 | 0.536 | 0.560 | 0.623 | 0.513 | 0.532 | 0.539 | 0.528 | 0.606 | 0.600 | 0.613 |
PNALT | 0.586 | 0.531 | 0.618 | 0.587 | 0.449 | 0.670 | 0.625 | 0.575 | 0.652 | 0.649 | 0.495 | 0.745 |
RPR | 0.654 | 0.681 | 0.640 | 0.729 | 0.725 | 0.735 | 0.654 | 0.668 | 0.652 | 0.750 | 0.730 | 0.764 |
RLR | 0.490 | 0.487 | 0.490 | 0.549 | 0.571 | 0.533 | 0.483 | 0.517 | 0.461 | 0.520 | 0.534 | 0.511 |
S index | 0.708 | 0.737 | 0.695 | 0.797 | 0.827 | 0.782 | 0.713 | 0.702 | 0.732 | 0.856 | 0.864 | 0.858 |
Virahep-C model | 0.652 | 0.687 | 0.636 | 0.707 | 0.768 | 0.686 | 0.694 | 0.737 | 0.693 | 0.771 | 0.737 | 0.826 |
Wang I | 0.700 | 0.766 | 0.680 | 0.791 | 0.838 | 0.786 | 0.705 | 0.774 | 0.689 | 0.859 | 0.894 | 0.854 |
Wang II | 0.695 | 0.725 | 0.678 | 0.758 | 0.809 | 0.726 | 0.663 | 0.678 | 0.658 | 0.769 | 0.769 | 0.772 |
XIE-model | 0.714 | 0.670 | 0.739 | 0.800 | 0.769 | 0.816 | 0.744 | 0.696 | 0.770 | 0.861 | 0.796 | 0.897 |
Group | Grade A (9–12 Points) | Grade B (5–8 Points) | Grade C (0–4 Points) |
---|---|---|---|
Total | APGA | AGPR, APRI, APPCI, APRG, FI, FIB-6, GAPI, GPR, GUCI, King’s score, Logit(Y), S index, Wang I, XIE-model | AA index, AAR, AARPRI, ABA, ALRI, AP index, APPR, ATPI model, CDS, Doha score, eLIFT, FCI, FIB-4, mFIB-4, FIB-5, FIB-6, FibroQ, Forns, Fibro-α, Gao-2, Gao-1, GqHBsR, GP, HB-F, HBeAg(+)model, HGM-1, HGM-2, IT model, INPR, Lok index, Mehdi’s model, NIKEI, NLR, PAPAS, PGA, PNALT, RPR, RLR, Virahep-C model, Wang II |
HBeAg(+)group | APGA, AGAP, GAPI, Gao-1Wang I | AGPR, APPCI, APRG, eLIFT, FIB-4 Forns, Gao-2, GPR, GUCI, S index King’s score, HBeAg(+) model, Wang II | AA index, AAR, AARPRI, ABA, ALRI, AP index, APRI, APPR, ATPI model, CDS, Doha score, FCI, FI, mFIB-4, FIB-5, FIB-6, FibroQ, Fibro-α, GqHBsR, GP, HB-F, HGM-1, HGM-2, IT model INPR, Lok index, Logit(Y), Mehdi’s model, NLR, NIKEI, PAPAS PGA, PNALT, RPR, RLR, Virahep-C model, XIE-model |
HBeAg(−)group | APGA, XIE-model | AGAP, APRI, APPCI, APRG, FI FIB-6, GAPI, GPR, GUCI, Logit(Y), King’s score, Mehdi’s model, S index Wang I | AA index, AAR, AARPRI, ABA, AGPR, ALRI, AP index, APPR ATPI model, CDS, Doha score, eLIFT, FCI, FIB-4, mFIB-4, FIB-5 FibroQ, Forns, Fibro-α, Gao-2, Gao-1, GqHBsR, GP HBeAg(+)model, HB-F, HGM-1, HGM-2, IT model, INPR, Lok index, NLR, NIKEI, PAPAS, PGA, PNALT, RPR, RLR Virahep-C model, Wang II |
Noninvasive Models or Indices | Inflammation Activity | Fibrosis Stage | Noninvasive Models or Indices | Inflammation Activity | Fibrosis Stage | ||||
---|---|---|---|---|---|---|---|---|---|
Spearman’s r | p Value | Spearman’s r | p Value | Spearman’s r | p Value | Spearman’s r | p Value | ||
AFP | 0.291 | <0.001 | 0.223 | <0.001 | GLB | 0.0.95 | 0.021 | 0.116 | 0.005 |
PT | 0.188 | <0.001 | 0.224 | <0.001 | PLT | −0.245 | <0.001 | −0.233 | <0.001 |
AST | 0.304 | <0.001 | 0.265 | <0.001 | N | −0.129 | 0.002 | −0.086 | 0.035 |
ALT | 0.207 | <0.001 | 0.139 | <0.001 | RDW-SD | 0.131 | 0.001 | 0.099 | 0.015 |
GGT | 0.251 | <0.001 | 0.255 | <0.001 | APGA | 0.452 | <0.001 | 0.405 | <0.001 |
ALP | 0.149 | <0.001 | 0.153 | <0.001 | GAPI | 0.331 | <0.001 | 0.352 | <0.001 |
DBIL | 0.081 | 0.051 | 0.140 | 0.001 | XIE-model | 0.392 | <0.001 | 0.344 | <0.001 |
ALB | −0.224 | <0.001 | −0.125 | <0.001 |
Models | AUROC (95% CI) | Cutoff | Se (%) | Sp (%) | PLR | NLR | PPV (%) | NPV (%) | p Value |
---|---|---|---|---|---|---|---|---|---|
S ≥ 2 | |||||||||
APGA | 0.750(0.702–0.798) | 6.72 | 69.1 | 69.8 | 2.2 | 0.4 | 52.2 | 82.5 | <0.001 |
GAPI | 0.719(0.674–0.763) | 1.81 | 52.7 | 82.3 | 2.8 | 0.6 | 57.5 | 78.1 | <0.001 |
XIE model | 0.714(0.668–0.761) | −0.94 | 61.5 | 74.2 | 2.2 | 0.6 | 51.6 | 78.5 | <0.001 |
S ≥ 3 | |||||||||
APGA | 0.832(0.778–0.885) | 7.27 | 76.8 | 73.4 | 3.1 | 0.3 | 28.4 | 95.8 | <0.001 |
GAPI | 0.802(0.746–0.858) | 1.84 | 74.6 | 77.4 | 3.3 | 0.4 | 28.5 | 95.7 | <0.001 |
XIE model | 0.800(0.736–0.850) | −0.72 | 74.2 | 75.4 | 3.0 | 0.4 | 27.2 | 95.6 | <0.001 |
G ≥ 2 | |||||||||
APGA | 0.779(0.734–0.823) | 6.72 | 70.8 | 70.8 | 2.3 | 0.4 | 52.2 | 83.6 | <0.001 |
GAPI | 0.705(0.658–0.751) | 1.86 | 50.5 | 83.5 | 3.0 | 0.6 | 57.6 | 78.0 | <0.001 |
XIE model | 0.744(0.697–0.790) | −0.69 | 56.8 | 83.0 | 3.2 | 0.5 | 59.1 | 80.1 | <0.001 |
G ≥ 3 | |||||||||
APGA | 0.874(0.823–0.926) | 8.53 | 65.9 | 91.8 | 7.1 | 0.4 | 42.1 | 96.3 | <0.001 |
GAPI | 0.834(0.776–0.892) | 1.91 | 77.6 | 79.5 | 3.5 | 0.3 | 24.4 | 97.4 | <0.001 |
XIE model | 0.861(0.806–0.917) | −0.43 | 79.2 | 81.0 | 4.3 | 0.3 | 28.7 | 97.5 | <0.001 |
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Ma, S.; Zhou, L.; Lin, S.; Li, M.; Luo, J.; Chen, L. Noninvasive Models to Assess Liver Inflammation and Fibrosis in Chronic HBV Infected Patients with Normal or Mildly Elevated Alanine Transaminase Levels: Which One Is Most Suitable? Diagnostics 2024, 14, 456. https://doi.org/10.3390/diagnostics14050456
Ma S, Zhou L, Lin S, Li M, Luo J, Chen L. Noninvasive Models to Assess Liver Inflammation and Fibrosis in Chronic HBV Infected Patients with Normal or Mildly Elevated Alanine Transaminase Levels: Which One Is Most Suitable? Diagnostics. 2024; 14(5):456. https://doi.org/10.3390/diagnostics14050456
Chicago/Turabian StyleMa, Shasha, Lian Zhou, Shutao Lin, Mingna Li, Jing Luo, and Lubiao Chen. 2024. "Noninvasive Models to Assess Liver Inflammation and Fibrosis in Chronic HBV Infected Patients with Normal or Mildly Elevated Alanine Transaminase Levels: Which One Is Most Suitable?" Diagnostics 14, no. 5: 456. https://doi.org/10.3390/diagnostics14050456