Circulating Receptor-Interacting Protein Kinase 3 Are Increased in HBV Patients With Acute-on-Chronic Liver Failure and Are Associated With Clinical Outcome

Liwen Chen; Zhujun Cao; Lei Yan; Yezhou Ding; Xinghua Shen; Kehui Liu; Xiaogang Xiang; Qing Xie; Chuanwu Zhu; Shisan Bao; Hui Wang

doi:10.3389/fphys.2020.00526

Circulating Receptor-Interacting Protein Kinase 3 Are Increased in HBV Patients With Acute-on-Chronic Liver Failure and Are Associated With Clinical Outcome

Front Physiol. 2020 Jun 16:11:526. doi: 10.3389/fphys.2020.00526. eCollection 2020.

Authors

Liwen Chen¹, Zhujun Cao¹, Lei Yan¹, Yezhou Ding¹, Xinghua Shen², Kehui Liu^{1

3}, Xiaogang Xiang¹, Qing Xie¹, Chuanwu Zhu², Shisan Bao⁴, Hui Wang¹

Affiliations

¹ Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Intensive Care Unit, The Affiliated Infectious Diseases Hospital of Soochow University, Jiangsu, China.
³ Department of Infectious Diseases, Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴ Discipline of Pathology, School of Medical Sciences and Bosch Institute, Charles Perkin Centre, University of Sydney, Sydney, NSW, Australia.

Abstract

Background and aims: Necroptosis is a newly identified type of cell death with programmed pathways. The current study was performed to investigate necroptosis by measuring its key regulators; receptor interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) in patients with Hepatitis B virus (HBV) related acute-on-chronic liver failure (ACLF).

Methods: HBV-related ACLF (HBV-ACLF) patients (n = 90), non-ACLF patients without cirrhosis (N = 70), patients with cirrhosis (N = 40), and healthy controls (HCs; n = 70) were enrolled in the study. All patients were subject to serum RIPK3 measurement. Hepatic RIPK3 and MLKL were also determined in the livers of 18 patients and five donors, using immunohistochemistry.

Results: Serum RIPK3 was significantly elevated in HBV-ACLF patients compared to that of non-ACLF patients and the HCs. Serum RIPK3 in ACLF patients at recruitment was significantly higher in non-survivors than those in survivors at the 90-day follow-up. The predictive accuracy of serum RIPK3 at the 90-day outcome was relatively good with an area under the receiver operating curve (AUROC) of 0.72 (p < 0.001), similar to that of the model of end-staged liver disease (MELD) score (0.76, p < 0.001). The combined use of RIPK3 and MELD score further increased the AUROC to 0.80. The hepatic RIPK3 and MLKL measured by immunohistochemistry, significantly increased in the patients with HBV-ACLF than in the patients without ACLF and the HCs.

Conclusion: Circulating RIPK3 was significantly increased in patients with HBV-ACLF and was associated with a clinical outcome. The improved combined objective scores could offer additional prognostic value in ACLF patients, for physicians with more accurate expectations.

Keywords: HBV; RIPK3; acute-on-chronic liver failure; cell death; necroptosis.