Prognostic value of M30/M65 for outcome of hepatitis B virus-related acute-on-chronic liver failure

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. (C) 2014 Baishideng Publishing Group Co., Limited. All rights reserved.

M2-like Kupffer cells in fibrotic liver may protect against acute insult

AIM To investigate the mechanism of hepatoprotection conferred by liver fibrosis through evaluating the activation phenotype of kupffer cells.METHODS Control and fibrotic mice were challenged with a lethal dose of D-Gal N/lipopolysaccharide(LPS),and hepatic damage was assessed by histology,serum alanine transferase(ALT)levels,and hepatic expression of HMGB1,a potent pro-inflammatory mediator.The localization of F4/80(a surrogate marker of KCs),HMGB1,and type I collagen(Col-1)was determined by immunofluorescence staining.The phenotype of KCs was characterized by real-time PCR.KCs isolated from control or fibrotic mice were challenged with LPS or HMGB1 peptide,and HMGB1 translocation was analyzed.RESULTS Liver fibrosis protected mice against D-Gal N/LPS challenge,as shown by improved hepatic histology and reduced elevation of ALT compared with the normal mice treated in the same way.This hepatoprotection was also accompanied by inhibition of HMGB1 expression in the liver.Co-localization of F4/80,HMGB1,and Col-1 was found in fibrotic livers,indicating the close relationship between KCs,HMGB1 and liver fibrosis.KCs isolated from fibrotic mice predominantly exhibited an M2-like phenotype.In vitro experiments showed that HMGB1 was localized in the nucleus of the majority of M2-like KCs and that the translocation of HMGB1 was inhibited following stimulation with LPS or HMGB1 peptide,while both LPS and HMGB1 peptide elicited translocation of intranuclear HMGB1 in KCs isolated from the control mice.CONCLUSION M2-like Kupffer cells in fibrotic liver may exert a protective effect against acute insult by inhibiting the translocation of HMGB1.