title: Prognostic value of M30/M65 for outcome of hepatitis B virus-related acute-on-chronic liver failure.
abstract: OBJECTIVE
  To determine the prognostic value of circulating indicators of cell death in acute-on-chronic liver failure (ACLF) patients with chronic hepatitis B virus (HBV) infection as the single etiology.
  
  
  METHODS
  Full length and caspase cleaved cytokeratin 18 (detected as M65 and M30 antigens) represent circulating indicators of necrosis and apoptosis. M65 and M30 were identified by enzyme-linked immunosorbent assay in 169 subjects including healthy controls (n = 33), patients with chronic hepatitis B (CHB, n = 55) and patients with ACLF (n = 81). According to the 3-mo survival period, ACLF patients were defined as having spontaneous recovery (n = 33) and non-spontaneous recovery which included deceased patients and those who required liver transplantation (n = 48).
  
  
  RESULTS
  Both biomarker levels significantly increased gradually as liver disease progressed (for M65: P < 0.001 for all; for M30: control vs CHB, P = 0.072; others: P < 0.001 for all). In contrast, the M30/M65 ratio was significantly higher in controls compared with CHB patients (P = 0.010) or ACLF patients (P < 0.001). In addition, the area under receiver operating characteristic curve (AUC) analysis demonstrated that both biomarkers had diagnostic value (AUC ≥ 0.80) in identifying ACLF from CHB patients. Interestingly, it is worth noting that the M30/M65 ratio was significantly different between spontaneous and non-spontaneous recovery in ACLF patients (P = 0.032). The prognostic value of the M30/M65 ratio was compared with the Model for End-Stage Liver Disease (MELD) and Child-Pugh scores at the 3-mo survival period, the AUC of the M30/M65 ratio was 0.66 with a sensitivity of 52.9% and the highest specificity of 92.6% (MELD:AUC = 0.71; sensitivity, 79.4%; specificity, 63.0%; Child-Pugh: AUC = 0.77; sensitivity, 61.8%; specificity, 88.9%).
  
  
  CONCLUSIONS
  M65 and M30 are strongly associated with liver disease severity. The M30/M65 ratio may be a potential prognostic marker for spontaneous recovery in patients with HBV-related ACLF.
authors.affiliation: Su-Jun Zheng, Shuang Liu, Mei Liu, Jun-Feng Li, Feng Ren, Yu Chen, Zhong-Ping Duan, Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Su-Jun
authors.initials: SJ
authors.lastname: Zheng
authors.affiliation: Su-Jun Zheng, Shuang Liu, Mei Liu, Jun-Feng Li, Feng Ren, Yu Chen, Zhong-Ping Duan, Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Liu
authors.affiliation: Su-Jun Zheng, Shuang Liu, Mei Liu, Jun-Feng Li, Feng Ren, Yu Chen, Zhong-Ping Duan, Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Liu
authors.affiliation: Su-Jun Zheng, Shuang Liu, Mei Liu, Jun-Feng Li, Feng Ren, Yu Chen, Zhong-Ping Duan, Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: McCrae
authors.affiliation: Su-Jun Zheng, Shuang Liu, Mei Liu, Jun-Feng Li, Feng Ren, Yu Chen, Zhong-Ping Duan, Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Jun-Feng
authors.initials: JF
authors.lastname: Li
authors.affiliation: Su-Jun Zheng, Shuang Liu, Mei Liu, Jun-Feng Li, Feng Ren, Yu Chen, Zhong-Ping Duan, Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Yuan-Ping
authors.initials: YP
authors.lastname: Han
authors.affiliation: Su-Jun Zheng, Shuang Liu, Mei Liu, Jun-Feng Li, Feng Ren, Yu Chen, Zhong-Ping Duan, Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Chun-Hui
authors.initials: CH
authors.lastname: Xu
authors.affiliation: Su-Jun Zheng, Shuang Liu, Mei Liu, Jun-Feng Li, Feng Ren, Yu Chen, Zhong-Ping Duan, Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Ren
authors.affiliation: Su-Jun Zheng, Shuang Liu, Mei Liu, Jun-Feng Li, Feng Ren, Yu Chen, Zhong-Ping Duan, Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Su-Jun Zheng, Shuang Liu, Mei Liu, Jun-Feng Li, Feng Ren, Yu Chen, Zhong-Ping Duan, Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Zhong-Ping
authors.initials: ZP
authors.lastname: Duan
mesh_terms: D065290:Acute-On-Chronic Liver Failure / Q000097:blood* / Q000175:diagnosis / Q000401:mortality / Q000628:therapy / Q000821:virology; D000328:Adult; D017209:Apoptosis; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D019694:Hepatitis B, Chronic / Q000097:blood* / Q000150:complications / Q000175:diagnosis / Q000401:mortality / Q000628:therapy; D006801:Humans; D053538:Keratin-18 / Q000097:blood*; D008099:Liver / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D010446:Peptide Fragments / Q000097:blood*; D011237:Predictive Value of Tests; D012372:ROC Curve; D012075:Remission, Spontaneous; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D053538:Keratin-18; C561463:M30 cytokeratin-18 peptide, human; C577325:M65 antigen, human; D010446:Peptide Fragments
keywords: Acute-on-chronic liver failure; Chronic hepatitis B virus infection; Liver disease severity; Liver disease stage; Prognostic value; Serum M30 level; Serum M65 level