Table 3.
Overview of the major studies on the use of microRNAs in hepatitis B virus infected patients for the staging of liver fibrosis
| Study group | Fibrosis staging/validation method | microRNA detection method/sample1 | Data normalization | microRNA regulation depending on fibrosis staging | microRNA panel for liver fibrosis | Ref. | ||
| 102 treatment naïve CHB | 58 pts F0-F2; 44 pts F3-F4 / liver biopsy and laboratory data | RT-qPCR / serum samples | Spiked-in cel-miR-39 | F3-F4 vs F0-F2 | miR-122, -27b | ↑ | miR-122, -222, PLT, ALP | Appourchaux et al[107], 2016 |
| miR-222, -224 | ↓ | |||||||
| 330 CHB, 165 HC | 165 pts F0-F3; 165 pts F4 / clinical and laboratory data | RT-qPCR / serum samples | Exogenous control using cel-miR-67 | CHB: F4 vs F0-F3 | miR-18a-5p, -21-5p, -29c-3p, -122-5p, -106b-5p, 185-5p | ↓ | Three panels: F4 vs other stages: miR-18a-5p, -21-5p -29c-3p, -122-5p, -106b-5p, 185-5p; F4 vs HC: miR-1, -146a-5p, -451a; CHB vs HC: miR-21-5p, -27a-3p -122-5p, -146a-5p | Jin et al[139], 2015 |
| CHB F4 vs HC | miR-1, -146a-5p | ↑ | ||||||
| miR-451a | ↓ | |||||||
| CHB vs HC | miR-21-5p, -27a-3p, -122-5p, -146a-5p | ↑ | ||||||
| 123 treatment naïve CHB | 69 pts F0-F2 vs 54 staged F3-F4 / liver biopsy | RT-qPCR; Serum samples | Spiked-in cel-miR-39 | F3-F4 vs F0-F2 | miR-29a, -143, -223, -21, -374 | ↓ | miR-29a, -143, -223, PLT | Bao et al[43], 2017 |
| 8 ASC, 8 AVH, 7 HC, 49 treatment naïve CHB | 49 CHB patients: 16 pts F0, 19 pts F1-F2, 14 pts F3-F4 / liver biopsy, clinical and laboratory data | RT-qPCR and microarray analysis; Serum samples | U6 RNA control relative miRNA | F1-F2 | miR-499-5p | ↑ | Analysis of miRNA networks and of individual MiRNA s | Singh et al[42], 2018 |
| miR-1227-3p | ↓ | |||||||
| F3-F4 | miR-34b-3p, -1224-3p, -1, -10b-5p, -20b-5p, -96b-5p, -133, -455-3p, -671-5p | ↑ | ||||||
| 19 CHB, 14 HC | 19 CHB pts with F0-F2 | RT-qPCR total plasma EVs/liver stiffness | Spiked-in cel-miR-39 | Plasma (F0-F2) | miR-192, -200b | ↑ | Expression pattern of each individual miRNA in EVs vs total plasma | Lambrecht et al[93], 2017 |
| EVs (F0-F2) | miR-192, -200b, -92a, -150 | ↓ | ||||||
| 207 CHB, 47 non-HBV-LC, 7 non-CHB, 137 HC | 207 CHB of which: 127 pts F4; 79 pts F0-F3 / liver biopsy | RT-qPCR / plasma samples | miR-1228 control with a log-2 scale transformation | CHB F4 and non-CHB F4; vs other groups; (panel for F4 diagnosis) | miR-106b | ↓ | Panel composed of miR-106 and miR-181b | Chen et al[44], 2013 |
| miR-181b | ↑ | |||||||
| 50 treatment naïve CHB | 10 pts F0, 10 pts F1, 10 pts F2, 10 pts F3, 10 pts F4 / liver biopsy | Microarray analysis / plasma samples | Log standardization of MiRNA s whose target gene expression levels > 2 folds and FDR < 0.05 | F4 vs F0 | miR-2861, -345-3p, -3620-3p, -3656, -371a-5p, -4646-5p, -4651, 4695-5p, -4800-5p, -638, | ↑ | Detailed differential expression of individual MiRNA s for each stage of liver fibrosis F0-F4 | Zhang et al[137], 2015 |
| miR-497-5p, -486-3p | ↓ | |||||||
| 92 CHB | 11 pts F0, 16 pts F1, 12 pts F2, 13 pts F3, 40 pts F4 / liver biopsy and laboratory data | RT-qPCR; Plasma samples | Quanto, EC1, EC2 controls; relative miRNA expression was assessed using 2−ΔΔCq calculation | ≥ F2 | miR-122-5p | ↑ | miR-122-5p, -21-5p, -146a-5p, -223, -29c-3p, -22-3p, -381-3p | Wang et al[106], 2018 |
| miR-223, -29c-3p | ↓ | |||||||
| ≥ F3 | miR-122-5p | ↑ | ||||||
| F4 vs F0 | miR-122-5p, -29c-3p, -146a-5p, -223 | -/↓ | ||||||
1
miRNA sample refers only to the samples collected from the serum/plasma in each of the mentioned studies. ↑ means upregulation. ↓ means downregulation. ALP: Alkaline phosphatase; ASC: Asymptomatic carriers; AVH: Acute viral hepatitis; CHB: Chronic hepatitis B; EVs: Extracellular vesicles; FDR: False discovery rate; HC: Healthy controls; LC: Liver cirrhosis; miR: MicroRNA; PLT: Platelet; Pts: Patients; RT-qPCR: Real time quantitative polymerase chain reaction.