The miRFIB-Score: A Serological miRNA-Based Scoring Algorithm for the Diagnosis of Significant Liver Fibrosis
Abstract
:1. Introduction
2. Materials and Methods
2.1. Animal Studies
2.2. Patient Cohort
2.3. Blood Collection
2.4. Serological Scoring of Fibrosis
2.5. Messenger RNA and microRNA Analysis
2.6. Histological Evaluation
2.7. Immunocytochemistry
2.8. Statistical Analysis
3. Results
3.1. Identification of Candidate HSC-Linked miRNAs
3.2. Identification of Ankrd52, Clcn5 and Peg10 as Potential Target Genes
3.3. miRNA Expression Analysis in the CCl4-Mouse Model
3.4. Patient Characteristics and Plasma miRNA Alterations During Liver Fibrosis Progression
3.5. Association of Circulating miRNAs With Clinical Variables
3.6. Discrimination of Significant Liver Fibrosis by the miRFIB-Score
3.7. Inclusion of PDGFRβ Improves the Diagnostic Power of the miRFIB-Score
4. Discussion
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Patient Cohorts | F0–1 | F2–4 | p Value |
---|---|---|---|
Individuals, n | 92 | 116 | |
Disease aetiology: n (%) | |||
Alcoholic liver disease | 6 (7%) | 27 (23%) | |
Viral liver disease | 46 (50%) | 28 (24%) | |
NAFLD | 40 (43%) | 61 (53%) | |
Characteristics | |||
Age (years): median (IQR) | 52 (42–63) | 57 (51–65) | 0.0003 |
Male, n (%) | 52 (57%) | 84 (72%) | 0.0267 |
BMI (kg/m2): median (IQR) | 27.44 (24.16–32.35) | 29.96 (25.18–34.23) | ns |
Laboratory parameters: median (IQR) | |||
AST (IU/L) | 34 (24–48) | 40 (28–67) | 0.0048 |
ALT (IU/L) | 43 (34–62) | 48 (32–71) | ns |
Alk Phos (IU/L) | 68 (54–87) | 87 (66–130) | <0.0001 |
GGT (IU/L) | 39 (23–83) | 71 (40–154) | <0.0001 |
Total bilirubin (mg/dL) | 0.60 (0.47–0.79) | 0.76 (0.57–1.20) | 0.0005 |
Albumin (g/L) | 43 (41–46) | 42 (39–45) | 0.0035 |
Thrombocytes (×103/mm3) | 231 (202–277) | 202 (149–255) | 0.0006 |
Creatinine (mg/dL) | 0.85 (0.70–1.02) | 0.87 (0.74–1.04) | ns |
Fibrosis scoring: median (IQR) | |||
AST/ALT ratio | 0.76 (0.62–0.87) | 0.82 (0.67–1.18) | 0.0211 |
APRI | 0.35 (0.24–0.57) | 0.56 (0.32–0.88) | 0.0005 |
Fib-4 | 1.13 (0.83–1.49) | 1.67 (1.08–2.80) | <0.0001 |
PRTA-score | 7.18 (4.49–9.87) | 11.63 (7.95–20.40) | <0.0001 |
miRNA-451a | miRNA-142-5p | Let-7f-5p | miRNA-378a-3p | miRNA-122-5p | miRNA-29a-3p | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
r | p | r | p | r | p | r | p | r | p | r | p | |
Age | −0.0409 | ns | −0.1602 | 0.0234 | 0.1416 | 0.0413 | 0.0905 | ns | 0.2628 | 0.0001 | 0.0096 | ns |
BMI | 0.0280 | ns | −0.0397 | ns | −0.1563 | 0.0287 | −0.1037 | ns | −0.0667 | ns | −0.2161 | 0.0025 |
AST | −0.1554 | 0.0318 | 0.0076 | ns | 0.1371 | ns | −0.1038 | ns | −0.2625 | 0.0002 | 0.1150 | ns |
ALT | −0.0727 | ns | 0.0207 | ns | 0.0534 | ns | −0.1412 | 0.0484 | −0.4093 | <0.0001 | −0.0166 | ns |
Alk Phos | −0.0022 | ns | −0.0804 | ns | 0.2027 | 0.0050 | −0.0047 | ns | 0.2059 | 0.0046 | 0.1600 | 0.0287 |
GGT | −0.1372 | ns | −0.1756 | 0.0174 | 0.1730 | 0.0163 | −0.0621 | ns | 0.0060 | ns | 0.0899 | ns |
Bilirubin | −0.0609 | ns | −0.0237 | ns | 0.3194 | <0.0001 | 0.1295 | ns | 0.1213 | ns | 0.2790 | 0.0001 |
Albumin | −0.1064 | ns | 0.0365 | ns | −0.2031 | 0.0067 | −0.0148 | ns | −0.2394 | 0.0014 | −0.1747 | 0.0207 |
Platelet count | 0.1243 | ns | −0.1139 | ns | −0.3778 | <0.0001 | −0.1629 | 0.0255 | −0.1050 | ns | −0.3514 | <0.0001 |
Creatinine | −0.0419 | ns | −0.0399 | ns | 0.0054 | ns | −0.0094 | ns | 0.0652 | ns | −0.0257 | ns |
AST/ALT | −0.1026 | ns | −0.0126 | ns | 0.0756 | ns | 0.0311 | ns | 0.1920 | 0.0072 | 0.1627 | 0.0234 |
Fib-4 | −0.1223 | ns | 0.0439 | ns | 0.3215 | <0.0001 | 0.1400 | ns | 0.0607 | ns | 0.2852 | 0.0001 |
APRI | −0.1551 | 0.0365 | 0.1039 | ns | 0.2820 | <0.0001 | 0.0321 | ns | −0.1573 | 0.0321 | 0.2551 | 0.0005 |
PRTA-score | −0.0559 | ns | 0.0266 | ns | 0.4332 | <0.0001 | 0.1479 | ns | 0.2401 | 0.0020 | 0.3447 | <0.0001 |
AUC | 95% CI | Optimal Cut-Off | Sensitivity (%) | Specificity (%) | PPV | NPV | |
---|---|---|---|---|---|---|---|
AST/ALT | |||||||
Derivation | 0.5936 | 0.4986–0.6886 | 0.6948 | 73.68 | 45.16 | 62.87 | 58.65 |
Validation | 0.5988 | 0.4546–0.7430 | 1.025 | 38.24 | 84.00 | 75.08 | 51.90 |
Total | 0.5956 | 0.5166–0.6747 | 0.8725 | 41.82 | 75.86 | 68.59 | 50.85 |
APRI | |||||||
Derivation | 0.6273 | 0.5313–0.7234 | 0.4928 | 59.46 | 68.97 | 70.72 | 57.44 |
Validation | 0.7128 | 0.5773–0.8482 | 0.7531 | 45.45 | 95.65 | 92.94 | 58.18 |
Total | 0.6481 | 0.5696–0.7267 | 0.4928 | 57.01 | 70.37 | 70.80 | 56.49 |
Fib-4 | |||||||
Derivation | 0.6773 | 0.5847–0.7698 | 1.505 | 61.11 | 73.68 | 74.53 | 60.05 |
Validation | 0.7083 | 0.5692–0.8474 | 1.520 | 58.06 | 86.96 | 84.88 | 62.19 |
Total | 0.6879 | 0.6112–0.7647 | 1.505 | 60.19 | 77.50 | 77.13 | 60.70 |
PRTA-score | |||||||
Derivation | 0.7399 | 0.6525–0.8272 | 10.36 | 59.15 | 81.63 | 80.23 | 61.32 |
Validation | 0.7912 | 0.6566–0.9258 | 7.842 | 86.21 | 72.22 | 79.64 | 80.60 |
Total | 0.7732 | 0.7033–0.8431 | 11.59 | 50.52 | 89.71 | 86.09 | 58.99 |
miRFIB | |||||||
Derivation | 0.7251 | 0.6393–0.8110 | 0.1109 | 77.33 | 61.40 | 71.63 | 68.24 |
Validation | 0.8173 | 0.7112–0.9235 | 0.3412 | 65.71 | 92.86 | 92.06 | 68.24 |
Total | 0.7558 | 0.6887–0.8229 | 0.1404 | 78.38 | 62.35 | 72.41 | 69.59 |
miRFIBp | |||||||
Derivation | 0.7912 | 0.7120–0.8704 | 0.0673 | 80.82 | 70.37 | 77.47 | 74.43 |
Validation | 0.8009 | 0.6844–0.9175 | 0.3840 | 68.75 | 81.48 | 82.39 | 67.41 |
Total | 0.7970 | 0.7329–0.8611 | 0.1043 | 79.05 | 69.51 | 76.57 | 72.47 |
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Lambrecht, J.; Verhulst, S.; Reynaert, H.; van Grunsven, L.A. The miRFIB-Score: A Serological miRNA-Based Scoring Algorithm for the Diagnosis of Significant Liver Fibrosis. Cells 2019, 8, 1003. https://doi.org/10.3390/cells8091003
Lambrecht J, Verhulst S, Reynaert H, van Grunsven LA. The miRFIB-Score: A Serological miRNA-Based Scoring Algorithm for the Diagnosis of Significant Liver Fibrosis. Cells. 2019; 8(9):1003. https://doi.org/10.3390/cells8091003
Chicago/Turabian StyleLambrecht, Joeri, Stefaan Verhulst, Hendrik Reynaert, and Leo A. van Grunsven. 2019. "The miRFIB-Score: A Serological miRNA-Based Scoring Algorithm for the Diagnosis of Significant Liver Fibrosis" Cells 8, no. 9: 1003. https://doi.org/10.3390/cells8091003