Animals ; Cytokines ; blood ; Endotoxins ; toxicity ; Fatty Liver ; chemically induced ; Liver Failure, Acute ; chemically induced ; Male ; Rats ; Rats, Sprague-Dawley

Animals ; Endotoxins ; Female ; HMGB1 Protein ; biosynthesis ; Liver Failure, Acute ; chemically induced ; metabolism ; Male ; Rats ; Rats, Wistar

Bee Venoms ; adverse effects ; Female ; Humans ; Insect Bites and Stings ; Liver Failure, Acute ; chemically induced ; Middle Aged

Objective: To explore the new mechanism of liver fibrosis through D-galactosamine/lipopolysaccharide (D-GalN/LPS)-induced necroptosis as an entry point to inhibit lethal injury. Methods: The carbon tetrachloride (CCl4)-induced mouse model of liver fibrosis was established. At 6 weeks of fibrosis, the mice were challenged with a lethal dose of D-GalN/LPS, and the normal mice treated with the same treatment were used as the control. The experiment was divided into four groups: control group (Control), acute injury group (D-GalN/LPS), liver fibrosis group (Fib), and liver fibrosis + acute challenge group (Fib + D-GalN/LPS). Quantitative PCR and immunofluorescence were used to analyze the expression of necroptosis key signal molecules RIPK1, RIPK3, MLKL and/or P-MLKL in each group. Normal mice were treated with inhibitors targeting key signaling molecules of necroptosis, and then given an acute challenge. The inhibitory effect of D-GalN/LPS-induced-necroptosis on acute liver injury was evaluated according to the changes in transaminase levels and liver histology. Liver fibrosis spontaneous ablation model was established, and then acute challenge was given. Necroptosis key signal molecules expression was analyzed in liver tissue of mice in each group and compared by immunohistochemistry. The differences between groups were compared with t-test or analysis of variance. Results: Quantitative PCR and immunofluorescence assays result showed that D-GalN/LPS-induced significant upregulation of RIPK1, RIPK3, MLKL and/or P-MLKL. Necroptosis key signal molecules inhibition had significantly reduced D-GalN/LPS-induced liver injury, as manifested by markedly reduced serum ALT and AST levels with improvement in liver histology. Necroptosis signaling molecules expression was significantly inhibited in fibrotic livers even under acute challenge conditions. Additionally, liver fibrosis with gradual attenuation of fibrotic ablation had inhibited D-GalN/LPS-induced necroptosis. Conclusion: Liver fibrosis may protect mice from acute lethal challenge injury by inhibiting D-GalN/LPS-induced necroptosis.
Animals ; Chemical and Drug Induced Liver Injury/pathology* ; Galactosamine/adverse effects* ; Lipopolysaccharides/adverse effects* ; Liver/pathology* ; Liver Cirrhosis/pathology* ; Liver Failure, Acute/chemically induced* ; Mice ; Necroptosis

Tetrachloroethylene is a chlorinated solvent that is primarily used in dry cleaning and degreasing operations. Although the hepatotoxicity caused by tetrachloroethylene has been well documented in literature, it is rarely considered as a cause of acute liver failure. We report a case of a 39-yr-old man who was admitted to our hospital for acute liver failure due to tetrachloroethylene exposure. Histological examination of the liver revealed massive hepatic necrosis, prominently, in zone 3 of the hepatic lobules. The patient underwent supportive treatment along with 3 sessions of plasmapheresis, and consequently, he presented a favorable outcome. Repeat liver biopsy performed 6 months after the patient's discharge showed architectural distortion with postnecrotic cirrhosis. Physicians should be aware of the possibility of acute liver failure induced by tetrachloroethylene. Early plasmapheresis can be effective for individuals with sufficient capacity for hepatocyte regeneration.
Adult ; Carcinogens/*toxicity ; Humans ; Liver Cirrhosis/pathology ; Liver Failure, Acute/chemically induced/*diagnosis/pathology ; Male ; *Occupational Exposure ; Plasmapheresis ; Tetrachloroethylene/*toxicity

Anti-Inflammatory Agents, Non-Steroidal ; adverse effects ; Chemical and Drug Induced Liver Injury ; etiology ; Humans ; Liver Failure, Acute ; chemically induced ; Sulfonamides ; adverse effects

Animals ; Disease Models, Animal ; Ephedra ; chemistry ; Galactosamine ; Lipopolysaccharides ; Liver Failure, Acute ; chemically induced ; drug therapy ; Protective Agents ; pharmacology ; Rats

To explore the prognostic factors for patients with drug-induced liver failure (DILF) and construct a logistic regression model (LRM).
 Methods: A retrospective analysis of clinical data was performed in 183 hospitalized patients, who were diagnosed with DILF in Xiangya Hospital, the Second Xiangya Hospital and the Third Xiangya Hospital, Central South University from January 2009 to January 2018. The patients were divided into an improved group (n=67) and an ineffective group (n=116) according to their prognosis. Univariate analysis was performed to screen for possible prognostic factors such as age, Tbil, SCr, PT and complications. According to the results of univariate analysis, the multivariate analysis was performed to determine the independent prognostic factors and construct a LRM. The LRM was compared with the model for end-stage liver disease (MELD), the predictive value of LRM and MELD was evaluated by receiver operating characteristic curve (ROC), the parameters such as area under the ROC (AUC) and total accuracy were compared between the 2 models and verified by another independent sample.
 Results: According to univariate analysis, there was significant differences in age, clinical type, hepatic encephalopathy, hepatorenal syndrome, WBC count, the ratio of aspartic acid transaminase (AST) to glutamine transaminase (ALT) (AST/ALT), Tbil, SCr, PT and alpha-fetoprotein (AFP) between the 2 groups (all P<0.05). Multivariate analysis revealed that: AFP, PT, AST/ALT, hepatic encephalopathy and hepatorenal syndrome were independent prognostic factors for DILF, which could be applied to constructing a LRM. The AUC of LRM and MELD was 0.917 (95% CI 0.876 to 0.959) and 0.709 (95% CI 0.633 to 0.786) respectively, the total accuracy rate of prediction for the LRM and the MELD was 86.7% and 68.3% respectively, there was significant difference in AUC and total accuracy rate between the LRM and the MELD (P<0.05). LRM was superior to MELD.
 Conclusion: AFP, PT, AST/ALT, hepatic encephalopathy and hepatorenal syndrome were independent prognostic factors for DILF; the LRM can well predict the prognosis in the DILF patients, which is superior to the MELD.
China ; Humans ; Liver Failure ; chemically induced ; diagnosis ; Logistic Models ; Predictive Value of Tests ; Prognosis ; ROC Curve ; Retrospective Studies ; Severity of Illness Index

To study the effect of endotoxin on liver apoptosis, L02 liver cells were cultured and passaged in vitro, and then stimulated by endotoxin at 10 mg/mL for 4, 8, 16 and 24 h respectively. Liver apoptosis was flow cytometrically and fluorescently detected. Immunohistochemistry was used to detect the delivery of smac and caspase9. The delivery of liver cell smac and the activity of caspase3 were measured by caspase3 assay kit. The hepatic failure models of rats were established by using D-galactosamine. The blood serum and liver tissues were collected for the detection of the liver function, the level of endotoxin and the activity of caspase3 by using chromogenic substrate limulus amebocyte lysate method (LAL) and caspase3 active assay kit. The expression of smac and caspase9 in liver cells was detected by Western blotting. With in vitro study, the L02 cells stimulated by LPS condensed into conglobation and formed apoptotic bodies. After those cells were stained by hoechst, the apoptotic cells displayed blue color under the fluorescent microscope. The apoptosis rate was increased over time and the apoptosis was mainly of advanced stage. Meanwhile, the rate of smac delivery and activity of caspase9 and caspase3 were increased on L02 cell membrane. In vivo, hepatic failure and obvious endotoxemia were induced by injection of more than 200 mg/kg D-GalN. Hepatic mitochondria smac was reduced with dosage of D-GalN and, on the contrary, the activity of caspase3 was increased. D-GalN at 200 mg/kg increased Caspase9 while D-GalN at 300 mg/kg decreased caspase9. Mitochondria signal channel plays an important role in the endotoxin-induced apoptosis of hepatic cells by promoting the release of smac from mitochondria to cytoplasm and activating caspase9 and caspase3 in its low-level channel.
Apoptosis/*drug effects ; Carrier Proteins/*metabolism ; Caspase 3/metabolism ; Caspase 9/metabolism ; Cell Line ; Cells, Cultured ; Endotoxins/*pharmacology ; Liver/cytology ; Liver/*metabolism ; Liver/pathology ; Liver Failure/chemically induced ; Liver Failure/pathology ; Mitochondrial Proteins/*metabolism ; Rats, Wistar

OBJECTIVETo investigate the etiology of 1977 patients from northern China with acute (ALF), sub-acute (SALF) or acute-on-chronic liver (ACLF) failures.

METHODThe age, gender, etiology, pathogenesis, and prognosis of the 1977 patients with liver failures were retrospectively analyzed.

RESULTSOf the 1977 cases, the three most common causes of ALF were HEV (33.96%) or HBV (13.21%) infections or those caused by medicines (9.43%). The three predominant causes of SALF were medicines (31.53%), HEV (16.22%) or HBV (9.91%) infections, but those of the ACLF were HBV (90.29%) infection, alcoholic hepatopathy (2.65%), and HBV super infected with HEV (2.26%) infections. 90.09% (1781) patients were infected by hepatotropic viruses. Of these 1781 patients, the most common cause of their liver failures was HBV infection (92.93%). In these HBV infected patients, 77.10% were from 26 to 55 years old. From 2005 to 2007, there were 39 patients with alcoholic liver failure. In the past two years, there were 23 patients with drug induced liver failure. The improvement rate of the 1977 patients after their treatments was 35.56%. The improvement rate of HEV infected liver failure was higher than drug induced liver failure (P less than 0.05); no statistical significance was found between other groups (P more than 0.05).

CONCLUSIONDifferent types of liver failure have different predominant causes. HBV infection is the most common cause in our 1977 patients. In the past two years, the number of drug induced liver failures and alcoholic liver failures have been increasing.

Acute Disease ; Adult ; Chemical and Drug Induced Liver Injury, Chronic ; etiology ; Chronic Disease ; Female ; Hepatitis B ; complications ; Hepatitis E ; complications ; Humans ; Liver Diseases, Alcoholic ; etiology ; Liver Failure ; chemically induced ; classification ; etiology ; virology ; Male ; Middle Aged ; Prognosis ; Retrospective Studies