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Acute‐on‐chronic liver failure (ACLF) is a life‐threatening syndrome with poor prognosis. Several studies have begun to prove that mitochondria play a crucial role in liver failure. Mitofusin2 (Mfn2) plays a key role in maintaining the integrity of mitochondrial morphology and function. However, the role and underlying mechanisms of Mfn2 on cell autophagy of ACLF remain unclear. Our aim was to explore the effect of Mfn2 on several biological functions involving cell autophagy in ACLF. In this study, we constructed an ACLF animal model and a hepatocyte autophagy model, using adenovirus and lentivirus to deliver Mfn2 to liver cells, in order to assess the effect of Mfn2 on autophagy and apoptosis in ACLF. Furthermore, we explored the biological mechanism of Mfn2‐induced autophagy of ACLF using Western blotting, RT‐PCR and electron microscopy. We found that Mfn2 significantly attenuated ACLF, characterized by ameliorated gross appearance and microscopic histopathology of liver, and reduced serum AST, ALT, and TBIL levels. Mfn2 improved the expressions of LC3‐II, Atg5 and Bcl‐2 and down‐regulated the expression of P62 and Bax in ACLF. Like rapamycin, Mfn2 also significantly inhibited the expressions of p‐PI3K, p‐Akt and p‐mTOR in ACLF. In conclusion, our findings suggest that Mfn2 influences multiple biological functions of ACLF via the PI3K/Akt/mTOR signalling pathway. This study will provide a reliable theoretical basis for the application of Mfn2 as an effective target for ACLF treatment, reversing or delaying the process of ACLF.

Introduction and Objectives Hypoxia-inducible factor-1α is critically involved in the pathogenesis of liver diseases. Its inhibitor genistein attenuated D-galactosamine (D-GalN)-induced liver damage. However, the role of genistein in acute-on-chronic liver failure (ACLF) is unclear. The influence of genistein on reactive oxygen species (ROS) and hepatocyte functions were evaluated in a rat model of ACLF. Material and methods Genistein [20 mg/ (kg. day)]/coenzyme Q10 [10 mg/ (kg. day)]/lipoic acid [20 mg/ (kg. day)] was administered via the intra-gastric route daily for 6 weeks as co-treatment to the rats in the experimental groups. Then, 100 μg/kg LPS combined with 0.5 g/kg D-GalN was injected intraperitoneally to attack the rats. Results Genistein significantly attenuated LPS/D-GalN-induced ACLF, characterized by ameliorated gross appearance and microscopic histopathology of liver, reduced AST level in serum, whereas increased levels of ATP, ADP/O, and respiratory control ratio (RCR) in mitochondria. Genistein suppressed necrosis and ROS production. Conclusion These results suggested that genistein could protect against ACLF through inhibiting cellular ROS production and necrosis, improving RCR, and decreasing permeability transition pores in mitochondrial, which was similar as mitochondrial protective agent coenzyme Q10.

BackgroundHepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a severe condition with high mortality due to lack of efficient therapy. Until now, the use of methylprednisolone (MP) in HBV-ACLF is still controversial. We aimed to evaluate the efficacy and safety of MP in HBV-ACLF.MethodsTotally 171 HBV-ACLF patients from three medical centers were randomly allocated into MP group (83 patients treated with MP intravenously guttae for 7 days plus standard treatment: 1.5 mg/kg/day [day 1–3], 1 mg/kg/day [day 4–5], and 0.5 mg/kg/day [day 6–7]) and control group (88 patients treated with standard treatment). The primary endpoints were 6-month mortality and prognostic factors for 6-month survival. The survival time, cause of death, adverse events, liver function, and HBV DNA replication were analyzed.ResultsThe 6-month mortality was significantly lower in MP group than control group [32.4% vs. 42.5%,P = 0.0037]. MP treatment was an independent prognostic factor for 6-month survival [HR (95% CI) 0.547(0.308–0.973);P = 0.040]. Factors associated with reduced 6-month mortality in MP group included HBV DNA and lymphocyte/monocyte ratio (LMR) (P P > 0.05).ConclusionsMP therapy is an effective and safe clinical strategy in HBV-ACLF, increasing the 6-month survival rate.Clinical trials registered athttp://www.chictr.org.cnas ChiCTR-TRC-13003113 registered on 16 March 2013.

Background Stem cell therapy has been applied in the treatment of acute-on-chronic liver failure (ACLF). However, its clinical efficiency is still debatable. The aim of this systematic review and meta-analysis is to evaluate the clinical efficiency of stem cell therapy in the treatment of ACLF. Methods The Cochrane Library, OVID, EMBASE, and PUBMED were searched to December 2017. Both randomized and non-randomized studies, assessing stem cell therapy in patients with ACLF, were included. The outcome measures were total bilirubin (TBIL), alanine transaminase (ALT), international normalized ratio (INR), albumin (ALB), and the model for end-stage liver disease (MELD) score. The quality of evidence was assessed by GRADEpro. Results Four randomized controlled trials and six non-randomized controlled trials were included. The TBIL levels significantly decreased at 1-, 3-, 12-month after the stem cell therapy (p = 0.0008; p = 0.04; p = 0.007). The ALT levels decreased significantly compared with the control group in the short-term (p

// Ran Xue 1, * , Zhonghui Duan 1, * , Haixia Liu 1 , Li Chen 2 , Hongwei Yu 1 , Meixin Ren 1 , Yueke Zhu 1 , Chenggang Jin 3 , Tao Han 4 , Zhiliang Gao 5 and Qinghua Meng 1 1 Department of Critical Care Medicine of Liver Disease, Beijing You-An Hospital, Capital Medical University, Beijing, China 2 Georgia Prevention Institute, Medical College of Georgia, Augusta University, Augusta, GA, USA 3 The School of Social Development and Public Policy, Beijing Normal University, Beijing, China 4 Department of Hepatology, Tianjin Third Central Hospital of Tianjin Medical University, Tianjin, China 5 Department of Infectious Diseases, The Third Affiliated Hospital, Zhongshan University, Guangzhou, China * These authors have contributed equally to this work Correspondence to: Qinghua Meng, email: meng_qh@126.com Keywords: acute-on-chronic liver failure; hepatitis B; prognostic model Received: October 06, 2017 Accepted: October 27, 2017 Published: November 14, 2017 ABSTRACT Aim: It is challenging to predict the outcome of patients with hepatitis B virus related acute-on-chronic liver failure (HBV-ACLF) through existing prognostic models. Our aim was to establish a novel dynamic model to improve the predictive efficiency of 30-day mortality in HBV-ACLF patients. Methods: 305 patients who were diagnosed as HBV-ACLF (derivation cohort, n=211; validation cohort, n=94) were included in this study. The HBV-ACLF dynamic (HBV-ACLFD) model was constructed based on the daily levels of predictive variables in 7 days after diagnosis combined with baseline risk factors by multivariate logistic regression analysis. The HBV-ACLFD model was compared with the Child-Turcotte-Pugh (CTP) score, end-stage liver disease (MELD) score, and MELD within corporation of serum sodium (MELD-Na) score by the area under the receiver-operating characteristic curves (AUROC). Results: The HBV-ACLFD model demonstrated excellent discrimination with AUROC of 0.848 in the derivation cohort and of 0.813 in the validation cohort (p=0.620). The performance of the HBV-ACLFD model appeared to be superior to MELD score, MELD-Na score and CTP score (P

Aims Glypican-3(GPC3) expression is correlated with poor prognosis and progression in hepatocellular carcinoma (HCC). HCC progression can be associated with the differentiation status of tumor cell before malignant transformation. Our aim was to investigate the dynamic expression of GPC3 during tumor cells differentiation and to explore the role and theoretical significance of GPC3 in malignant essence of HCC. Methods The expressions of tissue GPC3 and alpha-fetoprotein (AFP) were detected by immunohistochemical staining. The tumor size, lymph node involvement, and metastasis were determined by pathological and imaging studies. HepG2 cells were induced to differentiate by all-trans retinoic acid (ATRA). Differentiation was evaluated by cytokeratin 19(CK19), gamma glutamyl transferase(GGT) and AFP through reverse transcription-PCR (RT-PCR) and real-time PCR. GPC3 staining was analyzed through flow cytometry. Results Based on the immunohistochemical staining, the enrolled 316 cases were divided into two sub-types, namely GPC3 + HCC and GPC3 − HCC. Significant differences in morphology, histology variations, AFP expression, TNM staging and overall survival curves were observed between two sub-types. During HCC differentiation induced by ATRA, the mean value of GPC3 expression treated with ATRA was much lower than the ones in placebo. There were significant differences between GPC3 + HCC and GPC3-HCC for cumulative intrahepatic and extrahepatic recurrence in early stage HCC (P = 0.009, P = 0.010). Conclusions GPC3 is correlated with the clinical malignant behavior of HCC. Moreover, GPC3 phenotype changes from positive to negative during tumor cells differentiation. Meanwhile, GPC3 plays a significant role in tumor cellular origin theoretical system, which can better reflect the malignant essence of tumors.

Liver failure with hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome with high mortality. The aim of this study was to decipher clinical and laboratory characteristics of hemophagocytic lymphohistiocytosis after definite diagnosis of liver failure and to provide clues for early diagnosis and treatment of HLH in patients with liver failure. Eleven patients diagnosed with liver failure and HLH were retrospectively investigated in this study. All patients presented with jaundice, persistent high-grade fever, pancytopenia, splenomegaly, evidence of hemophagocytes in the bone marrow and laboratory abnormalities indicating HLH. The average interval from the earliest diagnosis of liver failure to a definitive diagnosis of HLH was 17.27 days. Six (54.55%) patients died during follow-up. For patients with liver failure after admission and subsequently definitively diagnosed with HLH, bilirubin and INR were significantly decreased. HLH is definitely diagnosed at an intermediate or late stage when patients have already suffered from liver failure. The initial dose of glucocorticoid (methylprednisolone) was decreased to 1–1.5 mg/kg/d and gradually reduced thereafter. In conclusion, for patients with liver failure, HLH should be screened as early as possible upon persistent fever, splenomegaly and unexplained pancytopenia. For patients with liver failure and HLH, the dosage of glucocorticoid should be reduced to avoid serious side effects.

Aim: Acute-on-chronic liver failure (ACLF) is closely related to mitochondrial dysfunction. Previous studies showed the vital role of mitofusin2 (Mfn2) in the regulation of mitochondrial function. However, the effect of Mfn2 on ACLF remains unknown. As one of mitochondrial-related pathways, BNIP3-mediated pathway controls the balance between apoptosis and autophagy. However, the relationship between Mfn2 and BNIP3-mediated pathway in ACLF is still obscure. The aim of our study is to clarify the effect of Mfn2 and potential molecular mechanisms in ACLF. Methods: We collected liver tissue from ACLF patients and constructed an ACLF animal model and a hepatocyte autophagy injury model, using adenovirus and lentivirus to deliver Mfn2 and Mfn2-siRNA to liver cells, in order to assess the effect of Mfn2 on autophagy and apoptosis in ACLF. We explored the biological mechanisms of Mfn2-induced autophagy and apoptosis of ACLF through Western blotting, Quantitative Real-Time PCR (RT-PCR), transmission electron microscopy, immunofluorescence, immunohistochemical staining, and hematoxylin–eosin staining. Results: Compared with the normal liver tissue, the expressions of Mfn2, Atg5, Beclin1, and LC3-II/I were significantly decreased and the expression of P62 was much higher in patients with ACLF. Mfn2 significantly attenuated ACLF, characterized via microscopic histopathology and reduced serum AST and ALT levels. Mfn2 promoted the expressions of ATP synthase β, Atg5, Beclin1, LC3-II/I, and Bcl2 and reduced the expressions of P62, Bax, and BNIP3. Conclusions: Mfn2 plays a protective role in the progression of ACLF. BNIP3-mediated signaling pathway is not the only factor associated with Mfn2 controlling the balance of apoptosis and autophagy in ACLF. Mfn2 will provide a promising therapeutic target for patients with ACLF.

It is still unknown that whether sepsis with hepatitis B virus related acute-on-chronic liver failure (HBV-ACLF) fit into the conventional diagnostic criteria of sepsis. Our aim was to investigate the potential clinical parameters for the diagnosis of HBV-ACLF with sepsis. A retrospective study was conducted in 43 patients with HBV-ACLF and sepsis who underwent orthotopic liver transplantation. All patients were divided into three groups according to the pathological results and laboratory test results. Immunohistochemistry (IHC) staining, hematoxylin-eosin (HE) staining and Gordon Sweet’s reticulin staining were performed in this study. Alanine aminotransferase (ALT), aspartale aminotransferase (AST), total bilirubin (TBiL), cholinesterase (CHE), albumin (ALB), prothrombin activity (PTA), blood routine examination were detected. The results being chosen at admission and before transplantation were analyzed. TBiL had a significant increase (563.5 ± 191.8 umol/L vs. 383.9 ± 157.6 umol/L, 438.3 ± 154.7 umol/L, P = 0.031) and ALT significantly decreased (81.6 ± 66.4 U/L, 754.5 ± 1084.7 U/L, 120.6 ± 102.5 U/L, P = 0.005) in sepsis group before liver transplantation. When sepsis appeared in patients with HBV-ACLF, the ratio of PLT to WBC count before liver transplantation was much lower than it at admission (4.6 ± 2.0 vs. 16.1 ± 7.2, P = 0.000). In conclusion, the clinical parameters of sepsis in patients with HBV-ACLF should be reset. The ratio of PLT/WBC and (WBCBLT/WBCAA)/ (PLTBLT/PLTAA) could remind us the occurring of sepsis in patients with HBV-ACLF.

This study aimed to determine if the immunoscore (IS) staging system would be a potential prognostic factor in hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) in China. IS was performed in a consecutive cohort of HBV-HCC patients (n= 92). CD3+, CD8+, and CD45RO+ T cells were quantified by immunohistochemical analyses. The patients were stratified into 5 IS groups: I0, I1, I2, I3, I4 for every 2 cell phenotypes (IS1 (CD8/CD45RO, IS2 (CD3/CD8), and IS3 (CD3/CD45RO), respectively. ImagePro Plus software was used in the calculation of the paraffin-embedded tumor sections. The staining of CD3+, CD8+, and CD45RO+ cells in the HBV-HCC tissue demonstrated that there were higher density and larger area of lymphocytes in the invasive margins (IM) region than in the center (CT). Univariate analysis showed that preoperative TNM staging (P = .01), serum gamma-glutamyl transpeptidase (GGT) level (P = .03), vascular invasion (P = .00), and density of CD3+T (CT) (P = 0.01) were correlated significantly with disease-free survival (DFS); serum alpha-fetoprotein (AFP) level (P = .02), tumor size (P = .00), serum cholinesterase (CHE) (P = .04), and GGT level (P = .01), density of CD3+T(CT) (P = .00), CD8+T(CT)(P = .00), CD45RO+T(CT) (P = .00), and CD45RO+T (IM) (P = .02) were correlated with overall survival (OS). Multivariate analysis showed that TNM staging was not an independent prognostic factor of DFS and OS. Our results showed ISs did not have a significantly correlation with DFS (P = .35, .19, and .07, respectively), but it was correlated significantly with OS (P = .00, .00, and .00, respectively). There were statistical differences among the OS of every ISs subgroup except I0 and I1 by the Cox regressions analysis. The IS staging was closely related to the outcome of patients. It can compensate the TNM tumor classification system in predicting the prognosis of HBV-HCC patients.