Receptor-Interacting Protein Kinase 3 (RIPK3) mRNA Levels Are Elevated in Blood Mononuclear Cells of Patients with Poor Prognosis of Acute-on-Chronic Hepatitis B Liver Failure

Receptor-Interacting Protein Kinase 3 (RIPK3) mRNA Levels Are Elevated in Blood Mononuclear Cells of Patients with Poor Prognosis of Acute-on-Chronic Hepatitis B Liver Failure

LIYAN HAN,^1,2 YUE TENG,¹ YUCHEN FAN,^1,2 SHUAI GAO,^1,2 FENG LI^1,2 and KAI WANG^1,2

¹Department of Hepatology, Qilu Hospital of Shandong University, Jinan, Shandong, China
²Institute of Hepatology, Shandong University, Jinan, Shandong, China

Necroptosis refers to a programmed form of necrosis, which involves the receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL). In this study, to investigate the role of necroptosis in the pathogenesis of acute-on-chronic hepatitis B liver failure (ACHBLF), we retrospectively analyzed 122 patients with ACHBLF, 131 patients with chronic hepatitis B (CHB), and 35 healthy controls (HCs). Using quantitative real-time polymerase chain reaction (RT-qPCR), we measured RIPK3 mRNA levels in peripheral blood mononuclear cells (PBMCs). ELISA was performed to measure the serum levels of MLKL, TNF-α and caspase-8. We found that RIPK3 mRNA levels were significantly higher in patients with ACHBLF than those with CHB or HCs. RIPK3 mRNA levels in patients with ACHBLF were positively correlated with serum levels of TNF-α or MLKL and negatively correlated with caspase-8 levels. Univariate and multivariate analysis revealed that RIPK3 mRNA level was predictive of 3-month mortality of ACHBLF. The area under receiver operating characteristic curve (AUC) of RIPK3 mRNA levels was 0.810 (95% CI: 0.729-0.876), which was higher than that of MELD scores (0.766, 95% CI: 0.681-0.838). The optimal cut-off point of 8.81 was determined for RIPK3 mRNA levels, which showed a sensitivity of 80.7% and a negative predictive value of 80.4%. These results indicate that elevated RIPK3 mRNA levels in PBMCs are associated with poor prognosis of ACHBLF. We thus propose that necroptosis may play an important role in pathogenesis of ACHBLF.

keywords —— acute-on-chronic hepatitis B liver failure; necroptosis; peripheral blood mononuclear cells; prognosis; receptor-interacting protein kinase 3

===============================

Tohoku J. Exp. Med., 2019, 247, 237-245

Correspondence: Kai Wang, M.D., Ph.D., Department of Hepatology, Qilu Hospital of Shandong University and Institute of Hepatology, Shandong University, 107^# Wenhuaxi Road, Jinan 250012, Shandong, China.

e-mail: wangdoc876@126.com; wangdoc2010@163.com