Copyright ©The Author(s) 2020.
World J Gastroenterol. Mar 21, 2020; 26(11): 1113-1127
Published online Mar 21, 2020. doi: 10.3748/wjg.v26.i11.1113
Table 1 Circulating and intrahepatic microRNA regulation and target processes involved in liver fibrogenesis in hepatitis B virus infection
MicroRNAPlasma levelLiver tissueMediated processes involved in liver fibrosisRef.
miR-34aCell-cycle regulator (cell differentiation, proliferation, metabolism, apoptosis); HSC activationGuo et al[45]; Singh et al[42]
miR-221 miR-222Collagen synthesis; HSC proliferation; Liver fibrosis; OncogenesisSingh et al[42]
miR 27a/bHSC activation, differentiation and proliferationZhang et al[131]
miR 181a/bCell cycle regulator; HSC activation and proliferationYu et al[132]
miR 199a/bHSC activationMurakami et al[91]
miR-223↓; ↓ EVsInflammatory responseAkamatsu et al[133]; Bao et al[43]; Ye et al[59]; Wang et al [106]
miR-125 (-125a-5p/ -125b)HSC activation, proliferationZheng et al[134]; You et al[49]
miR 21-5p↑in total plasma; ↓ in EVsCollagen synthesis; OncogenesisBao et al[43]; Wei et al[68]; Wang et al[135]
Table 2 Circulating microRNAs in hepatitis B virus infection and their significance for the staging of liver fibrosis
Circulating microRNAs, plasma or serumSignificance for liver diseaseRef.
Upregulated microRNAs
miR-185↑ in advanced (F3-F4) vs early liver fibrosis (F1-F2); and ↑ in early liver fibrosis vs healthy volunteers; No increase with HBV plasma DNALi et al[136]
miR-2861, miR-345-3p, miR-3620, miR-3656, miR-371a-5p, miR-4646-5p, miR-4651, miR-4695, miR-4800-5p, miR-638Individually ↑ in F1-F4 vs F0; Plasma expression differs between each stage of liver fibrosisZhang et al[137]
miR-1, mR-10b-5p, miR-20b-5p, miR-96b-5p, miR-133b, miR-455-ep, miR-671-5pIncrease in the serum in F3-F4 liver fibrosisSingh et al[42]
miR-499-5pIncreases in the serum in F1-F2 stagesSingh et al[42]
miR-106b, miR-181bPanel for the diagnosis of liver cirrhosis due both HBV and non-HBV associated infectionChen et al44]
Downregulated microRNAs
miR-29↓ in liver cirrhosis vs healthy controlsXing et al[138]; Wang et al[106]
miR-223↓ with the progression of liver fibrosis from F0-F2 to F3-F4Bao et al[43]; Wang et al[106]
miR-486-3p, miR-497-5pIndividually ↓ in F1-F4 vs F0; Plasma expression differs between each stage of liver fibrosisZhang et al[137]
miR-1227-3p↓ in the serum in F1-F2 stagesSingh et al[42]
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 groupFibrosis staging/validation methodmicroRNA detection method/sample1Data normalizationmicroRNA regulation depending on fibrosis stagingmicroRNA panel for liver fibrosisRef.
102 treatment naïve CHB58 pts F0-F2; 44 pts F3-F4 / liver biopsy and laboratory dataRT-qPCR / serum samplesSpiked-in cel-miR-39F3-F4 vs F0-F2miR-122, -27bmiR-122, -222, PLT, ALPAppourchaux et al[107], 2016
miR-222, -224
330 CHB, 165 HC165 pts F0-F3; 165 pts F4 / clinical and laboratory dataRT-qPCR / serum samplesExogenous control using cel-miR-67CHB: F4 vs F0-F3miR-18a-5p, -21-5p, -29c-3p, -122-5p, -106b-5p, 185-5pThree 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-5pJin et al[139], 2015
CHB F4 vs HCmiR-1, -146a-5p
CHB vs HCmiR-21-5p, -27a-3p, -122-5p, -146a-5p
123 treatment naïve CHB69 pts F0-F2 vs 54 staged F3-F4 / liver biopsyRT-qPCR; Serum samplesSpiked-in cel-miR-39F3-F4 vs F0-F2miR-29a, -143, -223, -21, -374miR-29a, -143, -223, PLTBao et al[43], 2017
8 ASC, 8 AVH, 7 HC, 49 treatment naïve CHB49 CHB patients: 16 pts F0, 19 pts F1-F2, 14 pts F3-F4 / liver biopsy, clinical and laboratory dataRT-qPCR and microarray analysis; Serum samplesU6 RNA control relative miRNA F1-F2miR-499-5pAnalysis of miRNA networks and of individual MiRNA sSingh et al[42], 2018
F3-F4miR-34b-3p, -1224-3p, -1, -10b-5p, -20b-5p, -96b-5p, -133, -455-3p, -671-5p
19 CHB, 14 HC19 CHB pts with F0-F2RT-qPCR total plasma EVs/liver stiffnessSpiked-in cel-miR-39Plasma (F0-F2)miR-192, -200bExpression pattern of each individual miRNA in EVs vs total plasmaLambrecht et al[93], 2017
EVs (F0-F2)miR-192, -200b, -92a, -150
207 CHB, 47 non-HBV-LC, 7 non-CHB, 137 HC207 CHB of which: 127 pts F4; 79 pts F0-F3 / liver biopsyRT-qPCR / plasma samplesmiR-1228 control with a log-2 scale transformationCHB F4 and non-CHB F4; vs other groups; (panel for F4 diagnosis)miR-106bPanel composed of miR-106 and miR-181bChen et al[44], 2013
50 treatment naïve CHB10 pts F0, 10 pts F1, 10 pts F2, 10 pts F3, 10 pts F4 / liver biopsyMicroarray analysis / plasma samplesLog standardization of MiRNA s whose target gene expression levels > 2 folds and FDR < 0.05F4 vs F0miR-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-F4Zhang et al[137], 2015
miR-497-5p, -486-3p
92 CHB11 pts F0, 16 pts F1, 12 pts F2, 13 pts F3, 40 pts F4 / liver biopsy and laboratory dataRT-qPCR; Plasma samplesQuanto, EC1, EC2 controls; relative miRNA expression was assessed using 2−ΔΔCq calculation≥ F2miR-122-5pmiR-122-5p, -21-5p, -146a-5p, -223, -29c-3p, -22-3p, -381-3pWang et al[106], 2018
miR-223, -29c-3p
≥ F3miR-122-5p
F4 vs F0miR-122-5p, -29c-3p, -146a-5p, -223-/↓
Table 4 Circulating microRNAs in hepatitis B virus infection and their role in necroinflammation vs fibrosis
Circulating microRNAmicroRNA regulationClinical significance in HBV infectionRef.
miR-122Correlates with the necroinflammatory activity, HBsAg and HBV DNA; Also correlated with ≥ F2 stage of liver fibrosisWaidmann et al[103], Ji et al[109], Wang et al[106]
miR-210Marker of necroinflammation; Varies with the severity of HBV hepatitisSong et al[140]
miR-125 (-125a-5p/ -125b)Correlates with HBV intrahepatic replication and necroinflammatory activityLi et al[141], Zheng et al[134]
miR-124Marker of HBV-associated necroinflammationWang et al[142]
miR-29Marker of liver fibrosis irrespective of aetiologyXing et al[139]
miR-223Marker of liver fibrosis, decreases with the progression to cirrhosisBao et al[43]
miR-185Increases in advanced HBV fibrosis; Could play a therapeutic role in HBV gene suppression in tumoral cellsLi et al[136], Fan et al[143]