Objective Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) pathophysiology remains unclear. This study aims to characterise the molecular basis of HBV-ACLF using transcriptomics.
Methods Four hundred subjects with HBV-ACLF, acute-on-chronic hepatic dysfunction (ACHD), liver cirrhosis (LC) or chronic hepatitis B (CHB) and normal controls (NC) from a prospective multicentre cohort were studied, and 65 subjects (ACLF, 20; ACHD, 10; LC, 10; CHB, 10; NC, 15) among them underwent mRNA sequencing using peripheral blood mononuclear cells (PBMCs).
Results The functional synergy analysis focusing on seven bioprocesses related to the PBMC response and the top 500 differentially expressed genes (DEGs) showed that viral processes were associated with all disease stages. Immune dysregulation, as the most prominent change and disorder triggered by HBV exacerbation, drove CHB or LC to ACHD and ACLF. Metabolic disruption was significant in ACHD and severe in ACLF. The analysis of 62 overlapping DEGs further linked the HBV-based immune-metabolism disorder to ACLF progression. The signatures of interferon-related, neutrophil-related and monocyte-related pathways related to the innate immune response were significantly upregulated. Signatures linked to the adaptive immune response were downregulated. Disruptions of lipid and fatty acid metabolism were observed during ACLF development. External validation of four DEGs underlying the aforementioned molecular mechanism in patients and experimental rats confirmed their specificity and potential as biomarkers for HBV-ACLF pathogenesis.
Conclusions This study highlights immune-metabolism disorder triggered by HBV exacerbation as a potential mechanism of HBV-ACLF and may indicate a novel diagnostic and treatment target to reduce HBV-ACLF-related mortality.
- liver failure
- hepatitis B
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Contributors JL (first author), XL, JJ and LY contributed equally. The study was designed by JL (last author) and XC. The manuscript was written by JL (last author), XC, JT, JL (first author), XL and DW. The experiments and data analysis were performed by JL (first author), XL, JJ, LY, JX, DS, YL, JL (8thauthor), KR, HH, JZ, PC, HY, JL (14th author), TW, LJ, PY, TL, HZ, SS, BG, XZ, QC, JC, XX, JH (26th author), SH, JH (28th author), SX, DW, JT, XC and JL (last author). JL (Last author) supported and supervised the project. All authors were involved in the critical revision of the manuscript.
Funding This study was supported by the National Natural Science Foundation of China (81830073), the National S&T Major Project of China (2017ZX10203201), the Zhejiang Provincial and State’s Key Project of Research and Development Plan of China (2016YFC1101303/4 and 2017C01026) and the National and Zhejiang Provincial special support programme for high-level personnel recruitment (Ten-thousand Talents Programme).
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval The study protocol was approved by the Clinical Research Ethics Committee of the First Affiliated Hospital, Zhejiang University School of Medicine (No. 2011-13). All patients and volunteers were well informed, and written consent was obtained from the study subjects or the legal surrogates of the patients before enrolment.
Data availability statement Data, that is raw reads from RNA-seq experiments in fastq files, are available in a public, open access repository without restrictions on the use or distribution of the data. The Sequence Read Archive database project accession number for accessing the data produced for this study is PRJNA548207 (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA548207/).
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