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Non-invasive assessment of liver fibrosis by serum metabolites in non-human primates and human patients

ABSTRACT: Summary Liver fibrosis, a rising cause of chronic liver diseases, could eventually develop into cirrhosis and liver failure. Current diagnosis of liver fibrosis relies on pathological examination of hepatic tissues acquired from percutaneous biopsy, which may produce invasive injuries. Here, for non-invasive assessment of liver fibrosis, we applied comparative multi-omics in non-human primates (rhesus macaques) and subsequent serum biopsy in human patients. Global transcriptomics showed significant gene enrichment of metabolism process, in parallel with oxidative stress and immune responses in fibrotic primates. Targeted metabolomics were concordant with transcriptomic patterns, identifying elevated lipids and porphyrin metabolites during hepatic fibrosis. Importantly, liquid biopsy results validated that specific metabolites in the serum (e.g., biliverdin) were highly diagnostic to distinguish human patients from healthy controls. Findings describe the interconnected transcriptional and metabolic network in primate liver fibrosis and provide potential indices for non-invasive detection of liver fibrosis in humans. Graphical abstract Highlights • Establishment of a robust liver fibrosis model in rhesus macaques• Comprehensive exploration of transcriptomic/metabolomic signatures of liver fibrosis• Non-invasive serum biopsy providing a potential approach for evaluating liver fibrosis• Preliminary evidence for biliverdin as a potential liver fibrosis biomarker Diagnostic technique in health technology; Nonclinical topic

SUBMITTER: Feng T

PROVIDER: S-EPMC10448158 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Project description:ObjectiveNon-invasive and accurate diagnostic tests for the screening of disease severity in non-alcoholic fatty liver disease (NAFLD) remain a major unmet need. Therefore, we aimed to examine if a combination of serum metabolites can accurately predict the presence of advanced fibrosis.DesignThis is a cross-sectional analysis of a prospective derivation cohort including 156 well-characterised patients with biopsy-proven NAFLD and two validation cohorts, including (1) 142 patients assessed using MRI elastography (MRE) and(2) 59 patients with biopsy-proven NAFLD with untargeted serum metabolome profiling.ResultsIn the derivation cohort, 23 participants (15%) had advanced fibrosis and 32 of 652 analysed metabolites were significantly associated with advanced fibrosis after false-discovery rate adjustment. Among the top 10 metabolites, 8 lipids (5alpha-androstan-3beta monosulfate, pregnanediol-3-glucuronide, androsterone sulfate, epiandrosterone sulfate, palmitoleate, dehydroisoandrosterone sulfate, 5alpha-androstan-3beta disulfate, glycocholate), one amino acid (taurine) and one carbohydrate (fucose) were identified. The combined area under the receiver operating characteristic curve (AUROC) of the top 10 metabolite panel was higher than FIB--4 and NAFLD Fibrosis Score (NFS) for the detection of advanced fibrosis: 0.94 (95% CI 0.897 to 0.982) versus 0.78 (95% CI0.674 to 0.891), p=0.002 and versus 0.84 (95% CI 0.724 to 0.929), p=0.017, respectively. The AUROC of the top 10 metabolite panel remained excellent in the independent validation cohorts assessed by MRE or liver biopsy: c-statistic of 0.94 and 0.84, respectively.ConclusionA combination of 10 serum metabolites demonstrated excellent discriminatory ability for the detection of advanced fibrosis in an derivation and two independent validation cohorts with greater diagnostic accuracy than the FIB-4-index and NFS. This proof-of-concept study demonstrates that a non-invasive blood-based diagnostic test can provide excellent performance characteristics for the detection of advanced fibrosis.

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Non-invasive assessment of liver fibrosis by serum metabolites in non-human primates and human patients

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