Transcriptomics unveils immune metabolic disruption and a novel biomarker of mortality in patients with HBV-related acute-on-chronic liver failure

Xi Liang; Peng Li; Jing Jiang; Jiaojiao Xin; Jinjin Luo; Jiaqi Li; Pengcheng Chen; Keke Ren; Qian Zhou; Beibei Guo; Xingping Zhou; Jiaxian Chen; Lulu He; Hui Yang; Wen Hu; Shiwen Ma; Bingqi Li; Xin Chen; Dongyan Shi; Jun Li; Chinese Group on the Study of Severe Hepatitis B (COSSH)

doi:10.1016/j.jhepr.2023.100848

Transcriptomics unveils immune metabolic disruption and a novel biomarker of mortality in patients with HBV-related acute-on-chronic liver failure

JHEP Rep. 2023 Jul 17;5(9):100848. doi: 10.1016/j.jhepr.2023.100848. eCollection 2023 Sep.

Authors

Xi Liang^{1

2}, Peng Li², Jing Jiang², Jiaojiao Xin², Jinjin Luo², Jiaqi Li², Pengcheng Chen³, Keke Ren², Qian Zhou², Beibei Guo², Xingping Zhou², Jiaxian Chen², Lulu He², Hui Yang², Wen Hu², Shiwen Ma², Bingqi Li², Xin Chen^{4

5}, Dongyan Shi², Jun Li^{1

2}; Chinese Group on the Study of Severe Hepatitis B (COSSH)

Affiliations

¹ Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, 318000, China.
² State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
³ Institute of Big Data and Artificial Intelligence in Medicine, School of Electronics and Information Engineering, Taizhou University, Taizhou, China.
⁴ Institute of Pharmaceutical Biotechnology and the First Affiliated Hospital, Department of Radiation Oncology, Zhejiang University School of Medicine, Hangzhou, China.
⁵ Joint Institute for Genetics and Genome Medicine between Zhejiang University and University of Toronto, Zhejiang University, Hangzhou, China.

Abstract

Background & aims: HBV-related acute-on-chronic liver failure (HBV-ACLF) is a complex syndrome associated with high short-term mortality. This study aims to reveal the molecular basis and identify novel HBV-ACLF biomarkers.

Methods: Seventy patients with HBV-ACLF and different short-term (28 days) outcomes underwent transcriptome sequencing using peripheral blood mononuclear cells. Candidate biomarkers were confirmed in two external cohorts using ELISA.

Results: Cellular composition analysis with peripheral blood mononuclear cell transcriptomics showed that the proportions of monocytes, T cells and natural killer cells were significantly correlated with 28-day mortality. Significant metabolic dysregulation of carbohydrate, energy and amino acid metabolism was observed in ACLF non-survivors. V-set and immunoglobulin domain-containing 4 (VSIG4) was the most robust predictor of patient survival (adjusted p = 1.74 × 10^-16; variable importance in the projection = 1.21; AUROC = 0.89) and was significantly correlated with pathways involved in the progression of ACLF, including inflammation, oxidative phosphorylation, tricarboxylic acid cycle and T-cell activation/differentiation. Plasma VSIG4 analysis externally validated its diagnostic value in ACLF (compared with chronic liver disease and healthy groups, AUROC = 0.983). The prognostic performance for 28-/90-day mortality (AUROCs = 0.769/0.767) was comparable to that of three commonly used scores (COSSH-ACLFs, 0.867/0.884; CLIF-C ACLFs, 0.840/0.835; MELD-Na, 0.710/0.737). Plasma VSIG4 level, as an independent predictor, could be used to improve the prognostic performance of clinical scores. Risk stratification based on VSIG4 expression levels (>122 μg/ml) identified patients with ACLF at a high risk of death. The generality of VSIG4 in other etiologies was validated.

Conclusions: This study reveals that immune-metabolism disorder underlies poor ACLF outcomes. VSIG4 may be helpful as a diagnostic and prognostic biomarker in clinical practice.

Impact and implications: Acute-on-chronic liver failure (ACLF) is a lethal clinical syndrome associated with high mortality. We found significant immune cell alterations and metabolic dysregulation that were linked to high mortality in patients with HBV-ACLF based on transcriptomics using peripheral blood mononuclear cells. We identified VSIG4 (V-set and immunoglobulin domain-containing 4) as a diagnostic and prognostic biomarker in ACLF, which could specifically identify patients with ACLF at a high risk of death.

Keywords: V-set and immunoglobulin domain-containing 4; acute-on-chronic liver failure; biomarker; mortality; transcriptomics.