Serum Keratin-18 Fragments as Cell Death Biomarker in Association with Disease Progression and Prognosis in Cirrhosis with HBV Infection

Abstract

Background & Aims: Extensive hepatocyte death leads to hepatic inflammation contributing to systemic inflammation and acute-on-chronic liver failure (ACLF) in alcoholc cirrhosis. We aimed to investigate hepatocyte death in relation to disease progression in cirrhosis with HBV infection. Methods: Cohort 1: 201 outpatients with stable chronic hepatitis B receving liver biopsy (152 non-cirrhotic and 49 cirrhotic). Cohort 2: 327 inpatients admitted for acute decompensation (AD) of cirrhosis. Cell death was determined with serum Keratin-18(K18) for total death and serum caspase-cleaved-K18(cK18) for apoptosis. Survival analyse was performed using competing risk method. Results: Serum K18 and cK18 were significantly (p<0.001) higher in patients from cohort 2 than those from cohort 1. Among cohort 2, ACLF patients had significantly (p<0.001) increased K18 and cK18 comparing to those without ACLF. Increased K18 and cK18 were mainly attributed to HBV flare-up, active alcoholism or other hepatic injury, and were associated with liver and coagulation failure. The tradition AD patients at dmission with upper-tertile of K18 or cK18 were at higher risk of developing ACLF during follow-up. Baseline serum K18 or cK18 was significantly associated with transplant-free 90-day survival independent of leukocytes, HBV DNA, bacterial infection, encephalopathy and severity scores. The combination of cell death biomarkers significantly improved the prognostic value of the currently established prognostic scores. The reduction of cell death level after standard treatment was associated with increased short-term survival. Conclusion: Measurements of serum K18 or cK18 in HBV decompensated cirrhosis is a promising tool for predicting ACLF and risk stratification of short-term outcome. Funding Statement: This work was supported by grants from the National Natural Science Foundation of China (81570560), Technology Supporting Project of the Science and Technology Commission Shanghai Municipality (16411960300), The Medical Science Research Foundation (YWJKJJHKYJJ-B17503), The Suzhou Expert Team of Clinical Medicine (SZYJTD201717), The Shanghai key project of Integrated Traditional Chinese and Western Medicine ZY (2018-2020)-FWTX-3001) and Key Projects in the National Science & Technology Pillar Program during the Thirteenth Five-year Plan Period (2018ZX10205504-001-002, 2018ZX10303501, 2017ZX10203201-008) Declaration of Interests: The authors declare: None. Ethics Approval Statement: The current study complies with the Declaration of Helsinki and has been approved by the Institutional Ethics Review Committee at Ruijin hospital. Written informed consents were obtained from all patients or their care givers with permission for samples to be used in this study. Sample storage and usage for research purposes was conducted according to the current national and institutional guidelines