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Circulating miRNAs as footprints for liver fibrosis grading in schistosomiasis.

ABSTRACT: BACKGROUND:Chronic infection with Schistosoma japonicum or S. mansoni results in hepatic fibrosis of the human host. Staging fibrosis is crucial for the prognosis and to determine the rapid need of treatment in patients with schistosomiasis. METHODS:To establish whether there is a correlation between circulating microRNA (miRNA) level and fibrosis progression in schistosomiasis, ten miRNAs were selected to assess their potential in grading schistosomiasis liver fibrosis. This was done firstly in two mouse strains (C57BL/6 and BALB/c) to determine the temporal expression profiles in serum over the course of S. japonicum infection, and then within a cohort of 163 schistosomiasis japonica patients with different grades of liver fibrosis. FINDING:Four miRNAs (miR-150-5p, let-7a-5p, let-7d-5p and miR-146a-5p) were able to distinguish patients with mild versus severe fibrosis. The level of serum miR-150-5p showed the most promising potential for grading hepatic fibrosis in schistosomiasis. The diagnostic performance of miR-150-5p in discriminating mild from severe fibrosis is comparable with that of the ELF test and serum HA level. In addition, the serum levels of the four miRNAs rebounded in infected C57BL/6 mice, after 6?months post treatment, following the regression of liver fibrosis, thereby providing further support for the utility of these miRNAs in grading schistosomal hepatic fibrosis. INTERPRETATION:Circulating miRNAs can be a supplementary tool for assessing hepatic fibrosis in human schistosomiasis. FUND: National Health and Medical Research Council (NHMRC) of Australia (APP1102926, APP1037304 and APP1098244).

SUBMITTER: Cai P

PROVIDER: S-EPMC6286190 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Circulating miRNAs as footprints for liver fibrosis grading in schistosomiasis.

Cai Pengfei P Mu Yi Y Olveda Remigio M RM Ross Allen G AG Olveda David U DU McManus Donald P DP

EBioMedicine 20181025

<h4>Background</h4>Chronic infection with Schistosoma japonicum or S. mansoni results in hepatic fibrosis of the human host. Staging fibrosis is crucial for the prognosis and to determine the rapid need of treatment in patients with schistosomiasis.<h4>Methods</h4>To establish whether there is a correlation between circulating microRNA (miRNA) level and fibrosis progression in schistosomiasis, ten miRNAs were selected to assess their potential in grading schistosomiasis liver fibrosis. This was ...[more]

PMID: 30482723

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Project description:IntroductionUltrasonography is widely used as the first tool to evaluate fatty liver disease, and the hepatorenal index is a semi-quantitative method that improves its performance. Fibrosis can co-exist with steatosis or even replace it during disease progression. This study aimed to evaluate the influence of fibrosis on the measurement of steatosis using the hepatorenal index.Materials and methodsThis cross-sectional study included 89 patients with nonalcoholic fatty liver disease and in whom liver fibrosis was determined by ultrasound elastography. The Pearson's correlation coefficient was used to compare between the results of the sonographic hepatorenal index and the quantification of steatosis using magnetic resonance spectroscopy as well the accuracy of detecting moderate to severe steatosis using sonography in two groups of patients: (A) without advanced fibrosis and (B) with advanced fibrosis. Advanced fibrosis was defined as a shear wave speed ≥ 1.78 m/s on ultrasound elastography. We calculated the area under the curve (AUC-ROC) to detect the ability of the hepatorenal index to differentiate light from moderate to severe steatosis in both groups. Moderate to severe steatosis was defined as a fat fraction > 15% on the magnetic resonance spectroscopy. The intra-observer variability was assessed using the Bland-Altman plot.ResultsAmong patients, the mean age was 54.6 years and 59.6% were women, 50.6% had a body mass index ≥ 30 kg/m2, 29.2% had moderate to severe steatosis, and 27.2% had advanced fibrosis. There was a correlation between steatosis grading by ultrasonography and magnetic resonance in group A (0.73; P < 0.001), but not in Group B (0.33; P = 0.058). The AUC-ROC for detecting a steatosis fraction ≥ 15% was 0.90 and 0.74 in group A and group B, respectively. The intra-observer variability for the hepatorenal index measurements was not significant (-0.036; P = 0.242).ConclusionThe hepatorenal index is not appropriate for estimating steatosis in livers with advanced fibrosis.

Project description:Introduction: Chronic hepatitis B (HBV) and C (HCV) virus infection is associated with the activation of hepatic stellate cells (HSCs) toward a myofibroblastic phenotype, resulting in excessive deposition of extracellular matrix, the development of liver fibrosis, and its progression toward cirrhosis. The gold standard for the detection and staging of liver fibrosis remains the liver biopsy, which is, however, associated with some mild and severe drawbacks. Other non-invasive techniques evade these drawbacks, but lack inter-stage specificity and are unable to detect early stages of fibrosis. We investigated whether circulating vesicle-associated miRNAs can be used in the diagnosis and staging of liver fibrosis in HBV and HCV patients. Methods: Plasma samples were obtained from 14 healthy individuals and 39 early stage fibrotic patients (F0-F2) with chronic HBV or HCV infection who underwent transient elastography (Fibroscan). Extracellular vesicles were extracted from the plasma and the level of miRNA-122, -150, -192, -21, -200b, and -92a was analyzed by qRT-PCR in total plasma and circulating vesicles. Finally, these same miRNAs were also quantified in vesicles extracted from in vitro activating primary HSCs. Results: In total plasma samples, only miRNA-200b (HBV: p = 0.0384; HCV: p = 0.0069) and miRNA-122 (HBV: p < 0.0001; HCV: p = 0.0007) were significantly up-regulated during early fibrosis. In circulating vesicles, miRNA-192 (HBV: p < 0.0001; HCV: p < 0.0001), -200b (HBV: p < 0.0001; HCV: p < 0.0001), -92a (HBV: p < 0.0001; HCV: p < 0.0001), and -150 (HBV: p = 0.0016; HCV: p = 0.004) displayed a significant down-regulation in both HBV and HCV patients. MiRNA expression profiles in vesicles isolated from in vitro activating primary mouse HSCs resembled the miRNA expression profile in circulating vesicles. Conclusion: Our analysis revealed a distinct miRNA expression pattern in total plasma and its circulating vesicles. The expression profile of miRNAs in circulating vesicles of fibrotic patients suggests the potential use of these vesicle-associated miRNAs as markers for early stages of liver fibrosis.

Project description:Schistosomiasis remains a major public health issue, with an estimated 230 million people infected worldwide. Novel tools for early diagnosis and surveillance of schistosomiasis are currently needed. Elevated levels of circulating microRNAs (miRNAs) are commonly associated with the initiation and progression of human disease pathology. Hence, serum miRNAs are emerging as promising biomarkers for the diagnosis of a variety of human diseases. This study investigated circulating host miRNAs commonly associated with liver diseases and schistosome parasite-derived miRNAs during the progression of hepatic schistosomiasis japonica in two murine models.Two mouse strains (C57BL/6 and BALB/c) were infected with a low dosage of Schistosoma japonicum cercariae. The dynamic patterns of hepatopathology, the serum levels of liver injury-related enzymes and the serum circulating miRNAs (both host and parasite-derived) levels were then assessed in the progression of schistosomiasis japonica. For the first time, an inverse correlation between the severity of hepatocyte necrosis and the level of liver fibrosis was revealed during S. japonicum infection in BALB/c, but not in C57BL/6 mice. The inconsistent levels of the host circulating miRNAs, miR-122, miR-21 and miR-34a in serum were confirmed in the two murine models during infection, which limits their potential value as individual diagnostic biomarkers for schistosomiasis. However, their serum levels in combination may serve as a novel biomarker to mirror the hepatic immune responses induced in the mammalian host during schistosome infection and the degree of hepatopathology. Further, two circulating parasite-specific miRNAs, sja-miR-277 and sja-miR-3479-3p, were shown to have potential as diagnostic markers for schistosomiasis japonica.We provide the first evidence for the potential of utilizing circulating host miRNAs to indicate different immune responses and the severity of hepatopathology outcomes induced in two murine strains infected with S. japonicum. This study also establishes a basis for the early and cell-free diagnosis of schistosomiasis by targeting circulating schistosome parasite-derived miRNAs.

Project description:Schistosomiasis affects approximately 240 million people in the world. Schistosoma mansoni eggs in the liver induce periportal fibrosis and hepatic failure driven by monocyte recruitment and macrophage activation, resulting in robust Th2 response. Here, we suggested a possible involvement of Galectin-3 (Gal-3), histone deacetylases (HDACs), and Hedgehog (Hh) signaling with macrophage activation during Th1/Th2 immune responses, fibrogranuloma reaction, and tissue repair during schistosomiasis. Gal-3 is highly expressed by liver macrophages (Kupffer cells) around Schistosoma eggs. HDACs and Hh regulate macrophage polarization and hepatic stellate cell activation during schistosomiasis-associated fibrogenesis. Previously, we demonstrated an abnormal extracellular matrix distribution in the liver that correlated with atypical monocyte-macrophage differentiation in S. mansoni-infected, Gal-3-deficient (Lgals3-/-) mice. New findings explored in this review focus on the chronic phase, when wild-type (Lgals3+/+) and Lgals3-/- mice were analyzed 90 days after cercariae infection. In Lgals3-/- infected mice, there was significant inflammatory infiltration with myeloid cells associated with egg destruction (hematoxylin and eosin staining), phagocytes (specifically Kupffer cells), numerically reduced and diffuse matrix extracellular deposition in fibrotic areas (Gomori trichrome staining), and severe disorganization of collagen fibers surrounding the S. mansoni eggs (reticulin staining). Granuloma-derived stromal cells (GR cells) of Lgals3-/- infected mice expressed lower levels of alpha smooth muscle actin (?-SMA) and eotaxin and higher levels of IL-4 than Lgals3+/+ mice (real-time PCR). The relevant participation of macrophages in these events led us to suggest distinct mechanisms of activation that culminate in defective fibrosis in the liver of Lgals3-/- infected mice. These aspects were discussed in this review, as well as the possible interference between Gal-3, HDACs, and Hh signaling during progressive liver fibrosis in S. mansoni-infected mice. Further studies focused on macrophage roles could elucidate these questions and clear the potential utility of these molecules as antifibrotic targets.

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Circulating miRNAs as footprints for liver fibrosis grading in schistosomiasis.

Publications

Circulating miRNAs as footprints for liver fibrosis grading in schistosomiasis.

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