Brief Article
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World J Gastroenterol. Mar 7, 2014; 20(9): 2403-2411
Published online Mar 7, 2014. doi: 10.3748/wjg.v20.i9.2403
Prognostic value of M30/M65 for outcome of hepatitis B virus-related acute-on-chronic liver failure
Su-Jun Zheng, Shuang Liu, Mei Liu, Malcolm A McCrae, Jun-Feng Li, Yuan-Ping Han, Chun-Hui Xu, Feng Ren, Yu Chen, Zhong-Ping Duan
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
Malcolm A McCrae, The Pirbright Institute, Pirbright GU24 ONF, United Kingdom
Jun-Feng Li, Department of Infectious Diseases, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
Yuan-Ping Han, The Center for Growth, Metabolism and Aging Research, College of Life Sciences, Sichuan University, Chengdu 610065, Sichuan Province, China
Chun-Hui Xu, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union of Medical College, Tianjin 300020, China
Author contributions: Zheng SJ and Liu S contributed equally to this work; Zheng SJ designed the study and performed the majority of experiments; Liu S designed the study and wrote the manuscript; Liu M and Ren F collected all the human materials; McCrae MA and Han YP revised the manuscript; Li JF and Xu CH analyzed the data; Chen Y and Duan ZP designed the study.
Supported by National Science and Technology Key Project of China on “Major Infectious Diseases”, No. 2012ZX10002004-006, No. 2012ZX10004904-003-001, No. 2013ZX10002002-006-001; Beijing Municipal Science and Technology Commission, No. Z131107002213019, No. Z131100004613030; High Technical Personnel Training Program in Beijing Health System, No. 2011-3-083, No. 2013-3-071; Special Scientific Research Fund for Beijing Health Development, No. 2011-2018-04; National Natural Science Foundation of China, No.30800979, No. 30800517
Correspondence to: Yu Chen, PhD, MD, Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, No. 8, Xitou Tiao Road, Youwai Street, Beijing 100069, China. chybeyond@163.com
Telephone: +86-10-63291007 Fax: +86-10-63295285
Received: September 21, 2013
Revised: December 31, 2013
Accepted: January 19, 2014
Published online: March 7, 2014
Abstract

AIM: 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%).

CONCLUSION: 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.

Keywords: Acute-on-chronic liver failure, Chronic hepatitis B virus infection, Liver disease stage, Liver disease severity, Serum M65 level, Serum M30 level, Prognostic value

Core tip: Massive hepatic cell death is a key characteristic of liver failure. Enzyme-linked immunosorbent assay was used to measure M65 and M30 in a chronic hepatitis B (CHB) infection cohort which included healthy controls, CHB and acute-on-chronic liver failure (ACLF) patients. Elevated M65 and M30 differentiated CHB or ACLF patients from healthy controls and gradually increased with disease severity. M30/M65 was significantly increased in ACLF patients with spontaneous recovery (P = 0.032), and the AUC of this ratio at the 3-mo survival period was 0.661 (sensitivity: 52.9%) with a high specificity (92.6%) compared with the Model for End-Stage Liver Disease and Child-Pugh scores.