State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China.
Gut. 2022 Jan;71(1):163-175. doi: 10.1136/gutjnl-2020-323395. Epub 2021 Jan 11.
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.
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).
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.
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.
乙型肝炎病毒相关慢加急性肝衰竭（HBV-ACLF）的发病机制仍不清楚。本研究旨在通过转录组学来描述 HBV-ACLF 的分子基础。
对来自前瞻性多中心队列的 400 例 HBV-ACLF、急性慢性肝功能障碍（ACHD）、肝硬化（LC）或慢性乙型肝炎（CHB）患者和正常对照（NC）进行研究，其中 65 例（ACLF 20 例，ACHD10 例，LC10 例，CHB10 例，NC15 例）进行了外周血单个核细胞（PBMCs）mRNA 测序。
针对与 PBMC 反应相关的七个生物过程的功能协同分析和前 500 个差异表达基因（DEGs）显示，病毒过程与所有疾病阶段都有关。免疫失调是乙型肝炎恶化触发的最显著的变化和紊乱，导致 CHB 或 LC 发展为 ACHD 和 ACLF。代谢紊乱在 ACHD 中明显，在 ACLF 中严重。对 62 个重叠 DEGs 的分析进一步将基于 HBV 的免疫代谢紊乱与 ACLF 进展联系起来。与先天免疫反应相关的干扰素相关、中性粒细胞相关和单核细胞相关途径的特征明显上调。与适应性免疫反应相关的特征下调。在 ACLF 发展过程中观察到脂质和脂肪酸代谢的破坏。在患者和实验大鼠中对上述分子机制下的四个 DEG 进行的外部验证证实了它们作为 HBV-ACLF 发病机制的生物标志物的特异性和潜力。
本研究强调了乙型肝炎病毒恶化引发的免疫代谢紊乱可能是 HBV-ACLF 的潜在机制，并可能为降低 HBV-ACLF 相关死亡率提供新的诊断和治疗靶点。
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