Hepatoprotective effects of cathepsin B inhibitor on acute hepatic failure induced by lipopolysaccharide/D-galactosamine in mice

BACKGROUND:Increasing evidence suggests that the inactivation of cathepsin B attenuates hepatocyte apoptosis and liver damage.This study aimed to investigate the protective effects of a cathepsin B inhibitor(CA-074me) on lipopolysaccharide(LPS)/D-galactosamine(D-GalN)-induced acute hepatic failure(AHF) in mice.METHODS:Mice were intraperitoneally injected with a combination of LPS/D-GalN to induce AHF with or without CA-074me pretreatment.The cumulative survival rates were calculated 48 hours after the induction of AHF.As well as changes in biochemical indicators and liver histology,hepatocyte apoptosis was assessed using a TUNEL method.Serum tumor necrosis factor-α(TNF-α) production,caspase-3,caspase-8,and caspase-9 activity was evaluated.Cytosolic cytochrome c and Bcl-2 expression were measured by Western blotting.RESULTS:The marked elevation in serum aminotransferase activity and prothrombin time found in LPS/D-GalN-treated mice was significantly improved by pretreatment with CA074me.The efficacy of CA-074me was also confirmed by histological analysis and TUNEL assay.The survival rate significantly improved in LPS/D-GalN-induced mice given CA-074me compared with untreated mice.LPS/D-GalNinduced caspase-3 and caspase-9 activation was remarkably suppressed by CA-074me.However,the increased levels of serum TNF-α and elevated caspase-8 activity in AHF mice were not significantly reduced by CA-074me.Moreover,CA074me sharply reduced the increased expression of cytosolic cytochrome c and markedly augmented Bcl-2 expression.CONCLUSION:These results suggest that CA-074me has a protective effect in acute hepatic failure induced by LPS/D-GalN.

Efficacy of liver transplantation for acute hepatic failure:asingle-center experience

BACKGROUND:Acute hepatic failure (AHF) is a devastating clinical syndrome with a high mortality rate.The outcome of AHF varies with etiology,but liver transplantation (LT) can significantly improve the prognosis and survival rate of such patients.This study aimed to detect the role of LT and artificial liver support systems (ALSS) for AHF patients and to analyze the etiology and outcome of patients with this disease.METHODS:A retrospective analysis was made of 48 consecutive patients with AHF who fulfilled the Kings College Criteria for LT at our center.We analyzed and compared the etiology,outcome,prognosis,and survival rates of patients between the transplantation (LT) group and the non-transplantation (N-LT) group.RESULTS:AHF was due to viral hepatitis in 25 patients (52.1%;hepatitis B virus in 22),drug or toxic reactions in 14 (29.2%;acetaminophen in 6),Wilson disease in 4 (8.3%),unknown reasons in 3 (6.3%),and miscellaneous conditions in 2 (4.2%).In the LT group,36 patients (7 underwent living donor LT,and 29 cadaveric LT) had an average model for endstage liver disease score (MELD) of 35.7.Twenty-eight patients survived with good graft function after a follow-up of 27.3± 4.5 months.During the waiting time,6 patients were treated with ALSS and 2 of them died during hospitalization.The 30-day,12-month,and 18-month survival rates were 77.8%,72.2%,and 66.7%,respectively.In the N-LT group,12 patients had an average MELD score of 34.5.Four patients were treated with ALSS and all died during hospitalization.The 90-day and 1-year survival rates were only 16.7% and 8.3%,respectively.CONCLUSIONS:Hepatitis is the most prominent cause of AHF at our center.Most patients with AHF,who fulfill the Kings College Criteria for LT,did not survive longer without LT.ALSS did not improve the prognosis of AHF patients,but may extend the waiting time for a donor.Currently,LT is still the most effective way to improve the prognosis of AHF patients.

Differential Gene Expression Profiles in Acute Hepatic Failure Model in Mice Infected with MHV-3 Virus Intervened by Anti-hepatic Failure Compound

Differential gene expression profiles in Balb/cJ mouse model of acute hepatic failure infected with MHV-3 virus intervened by anti-hepatic failure compound （AHFC） and the changes of cytokines regulated by genes were investigated. The Balb/cj mice were divided into AHFC-intervened group and control group randomly. Acute hepatic failure model of Balb/cJ mice infected with MHV-3 virus was established. The survival rate in the two groups was observed. It was found that the survival rate in the AHFC-intervened group and control group was 90% and 50% respectively 48 h after intraperitoneal injection of MHV-3 （P〈0.05）. Before and after the experiment, the cytokines in peripheral blood of the survival mice were determined, and RNA was extracted from survival mouse liver tissue for the analysis of the differential gene expression by a 36 kb mouse oligonuleotide DNA array. In all the genes of microarray there were 332 genes expressed differently in the two groups, in which 234 genes were up-regulated and 78 genes down-regulated. Through clustering analysis, the differential expression of immune related genes, including TNF receptor superfamily, Kctd9, Bcl-2, Fgl2, IL-8, IL-6, IFN-7, TNF-α etc. might be related with the curative effectiveness of AHFC. It was suggested that AHFC can balance the immune state of mouse model of acute hepatic failure infected with MHV-3 virus mainly through regulating the expression of immune related genes, decrease the immune damage and inhibit liver cell apoptosis of mouse acute hepatic failure model obviously so as to increase the survival rate of mouse models of acute hepatic failure.

Subacute fulminant hepatic failure with intermittent fever

BACKGROUND: Viral hepatitis B accounts for over 80% of acute hepatic failures in China and the patients die mainly of its complications. A patient with hepatic failure and fever is not uncommon, whereas repeated fever is rare. METHODS: A 32-year-old female was diagnosed with subacute hepatic failure and hepatitis B viral infection because of hyperbilirubinemia, coagulopathy, hepatic encephalopathy, serum anti-HBs-positive without hepatitis B vaccination, and typical intrahepatic pathological features of chronic hepatitis B. Plasma exchange was administered twice and she awoke with hyperbilirubinemia and discontinuous fever. RESULTS: Urethritis was confirmed and medication-induced fever and/or spontaneous bacterial peritonitis (Gram-negative bacillus infection) was suspected. The patient was treated with antibiotics, steroids and a Chinese herbal medicine, matrine, for three months and she recovered. CONCLUSION: The survival rate of patients with hepatic failure might be improved with comprehensive supporting measures and appropriate, timely management of complications.

Acute-on-chronic liver failure：recent update

Acute on chronic liver failure（ACLF） was first described in 1995 as a clinical syndrome distinct to classic acute decompensation.Characterized by complications of decompensation,ACLF occurs on a background of chronic liver dysfunction and is associated with high rates of organ failure and significant short-term mortality estimated between45%and 90%.Despite the clinical relevance of the condition,it still remains largely undefined with continued disagreement regarding its precise etiological factors,clinical course,prognostic criteria and management pathways.It is concerning that,despite our relative lack of understanding of the condition,the burden of ACLF among cirrhotic patients remains significant with an estimated prevalence of 30.9%.This paper highlights our current understanding of ACLF,including its etiology,diagnostic and prognostic criteria and pathophysiology.It is evident that further refinement of the ACLF classification system is required in order to detect high-risk patients and improve short-term mortality rates.The field of metabolomics certainly warrants investigation to enhance diagnostic and prognostic parameters,while the use of granulocyte-colony stimulating factor is a promising future therapeutic intervention for patients with ACLF.

Hepatitis E virus-related acute liver failure associated with pure red cell aplasia

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The Pathogenesis of Acute on Chronic Hepatitis B liver Failure

Acute-on-chronic liver failure is a characteristic clinical liver syndrome, which should be differentiated from acute liver failure, acute decompensated liver cirrhosis and chronic liver failure. The pathogenesis of ACLF is not fully understood yet. Viral factors and immune injury have been reported to be the two major pathogenesis. This paper reviewed the researches on the pathogenesis of acute on chronic hepatitis B liver failure in recent years, to provide theoretical basis for prompt and accurate diagnosis and treatment of this syndrome. This would benefit for the prognosis and raise the survival rate of patients.

Study on the role of autophagy in the occurrence and development of liver diseases

Autophagy is a process of lysosome degradation,which plays an important role in maintaining cell homeostasis and organ integrity through the degradation of misfolded proteins,removal of damaged organelles and excess lipids,which is one of the research hotspots in recent years.Liver disease often develops into chronic disease with high mortality,which seriously affects the life safety and quality of life of patients.Studies have shown that autophagy participates in the processes of cellular immunity and oxidative stress,plays an important role in a variety of liver diseases,has the characteristics of two-way regulation,and moderate autophagy has a protective effect.Excessive or dysfunctional autophagy can promote cell death and lead to the occurrence and development of the disease.at present,regulating autophagy is considered as a potential treatment.Based on chronic viral hepatitis,liver fibrosis,non-alcoholic fatty liver disease,acute liver failure and primary liver cancer,this paper reviews the functional characteristics and regulatory mechanism of autophagy in liver diseases.to explore new therapeutic targets for liver diseases,in order to provide new ideas and basis for clinical diagnosis and treatment.