AGK2 pre-treatment protects against thioacetamide-induced acute liver failure via regulating the MFN2-PERK axis and ferroptosis signaling pathway

Background:Acute liver failure(ALF)is an unpredictable and life-threatening critical illness.The pathological characteristic of ALF is massive necrosis of hepatocytes and lots of inflammatory cells infiltration which may lead to multiple organ failure.Methods:Animals were divided into 3 groups,normal,thioacetamide(TAA,ALF model)and TAA+AGK2.Cultured L02 cells were divided into 5 groups,normal,TAA,TAA+mitofusin 2(MFN2)-siRNA,TAA+AGK2,and TAA+AGK2+MFN2-siRNA groups.The liver histology was evaluated with hematoxylin and eosin staining,inositol-requiring enzyme 1(IRE1),activating transcription factor 6β(ATF6β),protein kinase R(PKR)-like endoplasmic reticulum kinase(PERK)and phosphorylated-PERK(p-PERK).C/EBP homologous protein(CHOP),reactive oxygen species(ROS),MFN2 and glutathione peroxidase 4(GPX4)were measured with Western blotting,and cell viability and liver chemistry were also measured.Mitochondriaassociated endoplasmic reticulum membranes(MAMs)were measured by immunofluorescence.Results:The liver tissue in the ALF group had massive inflammatory cell infiltration and hepatocytes necrosis,which were reduced by AGK2 pre-treatment.In comparison to the normal group,apoptosis rate and levels of IRE1,ATF6β,p-PERK,CHOP,ROS and Fe2+in the TAA-induced ALF model group were significantly increased,which were decreased by AGK2 pre-treatment.The levels of MFN2 and GPX4 were decreased in TAA-induced mice compared with the normal group,which were enhanced by AGK2 pretreatment.Compared with the TAA-induced L02 cell,apoptosis rate and levels of IRE1,ATF6β,p-PERK,CHOP,ROS and Fe2+were further increased and levels of MFN2 and GPX4 were decreased in the MFN2-siRNA group.AGK2 pre-treatment decreased the apoptosis rate and levels of IRE1,ATF6β,p-PERK,CHOP,ROS and Fe2+and enhanced the protein expression of MFN2 and GPX4 in MFN2-siRNA treated L02 cell.Immunofluorescence observation showed that level of MAMs was promoted in the AGK2 pre-treatment group when compared with the TAA-induced group in both mice and L02 cells.Conclusions:The data suggested that AGK2 pre-treatment had hepatoprotective role in TAA-induced ALF via upregulating the expression of MFN2 and then inhibiting PERK and ferroptosis pathway in ALF.

Silent information regulator sirtuin 1 ameliorates acute liver failure via the p53/glutathione peroxidase 4/gasdermin D axis

BACKGROUND Acute liver failure(ALF)has a high mortality with widespread hepatocyte death involving ferroptosis and pyroptosis.The silent information regulator sirtuin 1(SIRT1)-mediated deacetylation affects multiple biological processes,including cellular senescence,apoptosis,sugar and lipid metabolism,oxidative stress,and inflammation.AIM To investigate the association between ferroptosis and pyroptosis and the upstream regulatory mechanisms.METHODS This study included 30 patients with ALF and 30 healthy individuals who underwent serum alanine aminotransferase(ALT)and aspartate aminotransferase(AST)testing.C57BL/6 mice were also intraperitoneally pretreated with SIRT1,p53,or glutathione peroxidase 4(GPX4)inducers and inhibitors and injected with lipopolysaccharide(LPS)/D-galactosamine(D-GalN)to induce ALF.Gasdermin D(GSDMD)^(-/-)mice were used as an experimental group.Histological changes in liver tissue were monitored by hematoxylin and eosin staining.ALT,AST,glutathione,reactive oxygen species,and iron levels were measured using commercial kits.Ferroptosis-and pyroptosis-related protein and mRNA expression was detected by western blot and quantitative real-time polymerase chain reaction.SIRT1,p53,and GSDMD were assessed by immunofluorescence analysis.RESULTS Serum AST and ALT levels were elevated in patients with ALF.SIRT1,solute carrier family 7a member 11(SLC7A11),and GPX4 protein expression was decreased and acetylated p5,p53,GSDMD,and acyl-CoA synthetase long-chain family member 4(ACSL4)protein levels were elevated in human ALF liver tissue.In the p53 and ferroptosis inhibitor-treated and GSDMD^(-/-)groups,serum interleukin(IL)-1β,tumour necrosis factor alpha,IL-6,IL-2 and C-C motif ligand 2 levels were decreased and hepatic impairment was mitigated.In mice with GSDMD knockout,p53 was reduced,GPX4 was increased,and ferroptotic events(depletion of SLC7A11,elevation of ACSL4,and iron accumulation)were detected.In vitro,knockdown of p53 and overexpression of GPX4 reduced AST and ALT levels,the cytostatic rate,and GSDMD expression,restoring SLC7A11 depletion.Moreover,SIRT1 agonist and overexpression of SIRT1 alleviated acute liver injury and decreased iron deposition compared with results in the model group,accompanied by reduced p53,GSDMD,and ACSL4,and increased SLC7A11 and GPX4.Inactivation of SIRT1 exacerbated ferroptotic and pyroptotic cell death and aggravated liver injury in LPS/D-GalNinduced in vitro and in vivo models.CONCLUSION SIRT1 activation attenuates LPS/D-GalN-induced ferroptosis and pyroptosis by inhibiting the p53/GPX4/GSDMD signaling pathway in ALF.

Novel insights into autophagy in gastrointestinal pathologies,mechanisms in metabolic dysfunction-associated fatty liver disease and acute liver failure

In this editorial,we comment on three articles published in a recent issue of World Journal of Gastroenterology.There is a pressing need for new research on autophagy's role in gastrointestinal(GI)disorders,and also novel insights into some liver conditions,such as metabolic dysfunction-associated fatty liver disease(MAFLD)and acute liver failure(ALF).Despite advancements,understanding autophagy's intricate mechanisms and implications in these diseases remains incomplete.Moreover,MAFLD's pathogenesis,encompassing hepatic steatosis and metabolic dysregulation,require further elucidation.Similarly,the mechanisms underlying ALF,a severe hepatic dysfunction,are poorly understood.Innovative studies exploring the interplay between autophagy and GI disorders,as well as defined mechanisms of MAFLD and ALF,are crucial for identifying therapeutic targets and enhancing diagnostic and treatment strategies to mitigate the global burden of these diseases.

Understanding the molecular crossroads in acute liver failure:A pathway to new therapies

In this editorial we comment on the article published in a recent issue of the World Journal of Gastroenterology.Acute liver failure(ALF)is a critical condition characterized by rapid hepatocellular injury and organ dysfunction,and it often necessitates liver transplant to ensure patient survival.Recent research has eluci-dated the involvement of distinct cell death pathways,namely ferroptosis and pyroptosis,in the pathogenesis of ALF.Ferroptosis is driven by iron-dependent lipid peroxidation,whereas pyroptosis is an inflammatory form of cell death;both pathways contribute to hepatocyte death and exacerbate tissue damage.This comprehensive review explores the interplay between ferroptosis and pyroptosis in ALF,highlighting the role of key regulators such as silent information regulator sirtuin 1.Insights from clinical and preclinical studies provide valuable perspectives on the dysregulation of cell death pathways in ALF and the therapeutic potential of targeting these pathways.Collaboration across multiple disciplines is essential for translating the experimental insights into effective treatments for this life-threatening condition.

Acute liver failure:A clinically severe syndrome characterized by intricate mechanisms

Acute liver failure presents as a clinical syndrome characterized by swift deterioration and significant mortality rates.Its underlying mechanisms are intricate,involving intricate interplays between various cells.Given the current scarcity of treatment options,there's a pressing need to diligently uncover the disease's core mechanisms and administer targeted therapies accordingly.

Pylephlebitis-induced acute liver failure: A case report and review of literature

BACKGROUND Pylephlebitis is an extremely rare form of septic thrombophlebitis involving the portal vein,carrying high rates of morbidity and mortality.CASE SUMMARY We present a case of a 42-year-old male with no past medical history who presented with acute onset of abdominal pain and altered mental status with laboratory tests demonstrating new-onset acute liver failure.Pylephlebitis was determined to be the underlying etiology due to subsequent workup revealing polymicrobial gram-negative anaerobic bacteremia and complete thrombosis of the main and left portal veins.To our knowledge,this is the first documented case of acute liver failure as a potential life-threatening complication of pylephlebitis.CONCLUSION Our case highlights the importance of considering pylephlebitis in the broad differential for abdominal pain,especially if there are co-existing risk factors for hypercoagulability.We also demonstrate that fulminant hepatic failure in these patients can potentially be reversible with the immediate initiation of antibiotics and anticoagulation.

Construction of a predictive model for acute liver failure after hepatectomy based on neutrophil-to-lymphocyte ratio and albuminbilirubin score

BACKGROUND Acute liver failure(ALF)is a common cause of postoperative death in patients with hepatocellular carcinoma(HCC)and is a serious threat to patient safety.The neutrophil-to-lymphocyte ratio(NLR)is a common inflammatory indicator that is associated with the prognosis of various diseases,and the albumin-bilirubin score(ALBI)is used to evaluate liver function in liver cancer patients.Therefore,this study aimed to construct a predictive model for postoperative ALF in HCC tumor integrity resection(R0)based on the NLR and ALBI,providing a basis for clinicians to choose appropriate treatment plans.AIM To construct an ALF prediction model after R0 surgery for HCC based on NLR and ALBI.METHODS In total,194 patients with HCC who visited The First People’s Hospital of Lianyungang to receive R0 between May 2018 and May 2023 were enrolled and divided into the ALF and non-ALF groups.We compared differences in the NLR and ALBI between the two groups.The risk factors of ALF after R0 surgery for HCC were screened in the univariate analysis.Independent risk factors were analyzed by multifactorial logistic regression.We then constructed a prediction model of ALF after R0 surgery for HCC.A receiver operating characteristic curve,calibration curve,and decision curve analysis(DCA)were used to evaluate the value of the prediction model.RESULTS Among 194 patients with HCC who met the standard inclusion criteria,46 cases of ALF occurred after R0(23.71%).There were significant differences in the NLR and ALBI between the two groups(P<0.05).The univariate analysis showed that alpha-fetoprotein(AFP)and blood loss volume(BLV)were significantly higher in the ALF group compared with the non-ALF group(P<0.05).The multifactorial analysis showed that NLR,ALBI,AFP,and BLV were independent risk factors for ALF after R0 surgery in HCC.The predictive efficacy of NLR,ALBI,AFP,and BLV in predicting the occurrence of ALT after R0 surgery for HCC was average[area under the curve(AUC)NLR=0.767,AUCALBI=0.755,AUCAFP=0.599,AUCBLV=0.718].The prediction model for ALF after R0 surgery for HCC based on NLR and ALBI had a better predictive efficacy(AUC=0.916).The calibration curve and actual curve were in good agreement.DCA showed a high net gain and that the model was safer compared to the curve in the extreme case over a wide range of thresholds.CONCLUSION The prediction model based on NLR and ALBI can effectively predict the risk of developing ALF after HCC R0 surgery,providing a basis for clinical prevention of developing ALF after HCC R0 surgery.

Dengue induced acute liver failure:A meta summary of case reports

BACKGROUND Dengue fever is the most common cause of viral hemorrhagic fever,with more than 400 million cases being reported annually,worldwide.Even though hepatic involvement is common,acute liver failure(ALF)is a rare complication of dengue fever.AIM To analyze the demographic profile,symptomology,hospital course and outcomes of patients presenting with ALF secondary to dengue infection by reviewing the published case reports.METHODS A systematic search was performed from multiple databases including PubMed,Reference Citation Analysis,Science Direct,and Google Scholar.The search terms used were"dengue"OR"severe dengue"OR"dengue shock syndrome"OR"dengue haemorrhagic syndrome"OR"dengue fever"AND"acute liver failure"OR"hepatic failure"OR"liver injury".The inclusion criteria were:(1)Case reports or case series with individual patient details;(2)Reported acute liver failure secondary to dengue infection;and(3)Published in English language and on adult humans.The data were extracted for patient demographics,clinical sympto-matology,clinical interventions,hospital and intensive care unit course,need for organ support and clinical outcomes.RESULTS Data from 19 case reports fulfilling the predefined inclusion criteria were included.The median age of patients was 38 years(inter quartile range:Q3-Q126.5 years)with a female preponderance(52.6%).The median days from diagnosis of dengue to development of ALF was 4.5 d.The increase in aspartate aminotransferase was higher than that in alanine aminotransferase(median 4625 U/L vs 3100 U/L).All the patients had one or more organ failure,with neurological failure present in 73.7%cases.42.1%patients required vasopressor support and hepatic enceph-alopathy was the most reported complication in 13(68.4%)cases.Most of the patients were managed conser-vatively and 2 patients were taken up for liver transplantation.Only 1 death was reported(5.3%).CONCLUSION Dengue infection may rarely lead to ALF.These patients may frequently require intensive care and organ support.Even though most of these patients may improve with supportive care,liver transplantation may be a therapeutic option in refractory cases.

Stress granules inhibit endoplasmic reticulum stress-mediated apoptosis during hypoxia-induced injury in acute liver failure

BACKGROUND Stress granules(SGs)could be formed under different stimulation to inhibit cell injury.AIM To investigate whether SGs could protect hepatocytes from hypoxia-induced damage during acute liver failure(ALF)by reducing endoplasmic reticulum stress(ERS)mediated apoptosis.METHODS The agonist of SGs,arsenite(Ars)was used to intervene hypoxia-induced hepatocyte injury cellular model and ALF mice models.Further,the siRNA of activating transcription factor 4(ATF4)and SGs inhibitor anisomycin was then used to intervene in cell models.RESULTS With the increase of hypoxia time from 4 h to 12 h,the levels of HIF-1α,ERS and apoptosis gradually increased,and the expression of SGs marker G3BP1 and TIA-1 was increased and then decreased.Compared with the hypoxia cell model group and ALF mice model,the levels of HIF-1α,apoptosis and ERS were increased in the Ars intervention group.After siRNA-ATF4 intervention,the level of SGs in cells increased,and the levels of HIF-1α,ERS and apoptosis decreased.Compared with the siRNA-ATF4 group,the levels of G3BP1 in the siRNAATF4+anisomycin group were decreased,and the levels of HIF-1α,ERS and apoptosis were increased.Moreover,compared with the ALF group,the degree of liver injury and liver function,the levels of HIF-1α,ERS and apoptosis in the Ars intervention group were decreased,the level of SGs was increased.CONCLUSION SGs could protect hepatocytes from hypoxia-induced damage during ALF by reducing ERSmediated apoptosis.

MicroRNA-29a-3p Prevents Drug-Induced Acute Liver Failure through Inflammation-Related Pyroptosis Inhibition

Objective Little is known about the role of microRNA-29a-3p(miR-29a-3p)in inflammation-related pyroptosis,especially in drug-induced acute liver failure(DIALF).This study aimed to identify the relationship between miR-29a-3p and inflammation-related pyroptosis in DIALF and confirm its underlying mechanisms.Methods Thioacetamide(TAA)-and acetaminophen(APAP)-induced ALF mouse models were established,and human samples were collected.The expression levels of miR-29a-3p and inflammation and pyroptosis markers were measured by quantitative real-time polymerase chain reaction(qRT-PCR),Western blotting,or immunochemical staining in miR-29a-3p knock-in transgenic mouse(MIR29A(KI/KI))DIALF models.In addition,RNA sequencing was conducted to explore the mechanisms.Results MiR-29a-3p levels were decreased in TAA-and APAP-induced DIALF models.MiR-29a-3p prevented DIALF caused by TAA and APAP.RNA sequencing and further experiments showed that the protective effect of miR-29a-3p on DIALF was mainly achieved through inhibition of inflammation-related pyroptosis,and the inhibition was dependent on activation of the PI3K/AKT pathway.In addition,miR-29a-3p levels were reduced,and pyroptosis was activated in both peripheral blood mononuclear cells and liver tissues of DIALF patients.Conclusion The study supports the idea that miR-29a-3p inhibits pyroptosis by activating the PI3K/AKT pathway to prevent DIALF.MiR-29a-3p may be a promising therapeutic target for DIALF.

Acute liver failure:A systematic review and network meta-analysis of optimal type of stem cells in animal models

BACKGROUND The therapeutic effects of various stem cells in acute liver failure(ALF)have been demonstrated in preclinical studies.However,the specific type of stem cells with the highest therapeutic potential has not been determined.AIM To validate the efficacy of stem cells in ALF model and to identify the most promising stem cells.METHODS A search was conducted on the PubMed,Web of Science,Embase,Scopus,and Cochrane databases from inception to May 3,2022,and updated on November 16,2022 to identify relevant studies.Two independent reviewers performed the literature search,identification,screening,quality assessment,and data extraction.RESULTS A total of 89 animal studies were included in the analysis.The results of traditional meta-analysis showed that stem cell therapy could significantly reduce the serum levels of alanine aminotransferase[weighted mean difference(WMD)=-181.05(-191.71,-170.39)],aspartate aminotransferase[WMD=-309.04(-328.45,-289.63)],tumor necrosis factor-alpha[WMD=-8.75(-9.93,-7.56)],and interleukin-6[WMD=-10.43(-12.11,-8.76)]in animal models of ALF.Further subgroup analysis and network meta-analysis showed that although mesenchymal stem cells are the current research hotspot,the effect of liver stem cells(LSCs)on improving liver function is significantly better than that of the other five types of stem cells.In addition,the ranking results showed that the possibility of LSCs improving liver function ranked first.This fully proves the great therapeutic potential of LSCs,which needs to be paid more attention in the future.CONCLUSION LSCs may have a higher therapeutic potential.Further high-quality animal experiments are needed to explore the most effective stem cells for ALF.

Long-term outcomes of pediatric liver transplantation in acute liver failure vs end-stage chronic liver disease:A retrospective observational study

BACKGROUND Children with acute liver failure(ALF)who meet the criteria are eligible for super-urgent transplantation,whereas children with end-stage chronic liver disease(ESCLD)are usually transplanted electively.Pediatric liver transplantation(PLT)in ALF and ESCLD settings has been well described in the literature,but there are no studies comparing the outcomes in these two groups.AIM To determine if there is a difference in post-operative complications and survival outcomes between ALF and ESCLD in PLT.METHODS This was a retrospective observational study of all primary PLTs performed at a single center between 2000 and 2019.ALF and ESCLD groups were compared for pretransplant recipient,donor and operative parameters,and post-operative outcomes including graft and patient survival.RESULTS Over a 20-year study period,232 primary PLTs were performed at our center;195 were transplanted for ESCLD and 37 were transplanted for ALF.The ALF recipients were significantly older(median 8 years vs 5.4 years;P=0.031)and heavier(31 kg vs 21 kg;P=0.011).Living donor grafts were used more in the ESCLD group(34 vs 0;P=0.006).There was no difference between the two groups concerning vascular complications and rejection,but there were more bile leaks in the ESCLD group.Post-transplant patient survival was significantly higher in the ESCLD group:1-,5-,and 10-year survival rates were 97.9%,93.9%,and 89.4%,respectively,compared to 78.3%,78.3%,and 78.3%in the ALF group(P=0.007).However,there was no difference in 1-,5-,and 10-year graft survival between the ESCLD and ALF groups(90.7%,82.9%,77.3%vs 75.6%,72.4%,and 66.9%;P=0.119).CONCLUSION Patient survival is inferior in ALF compared to ESCLD recipients;the main reason is death in the 1st year post-PLT in ALF group.Once the ALF children overcome the 1st year after transplant,their survival stabilizes,and they have good long-term outcomes.

A bioartificial transgenic porcine whole liver expressing human proteins alleviates acute liver failure in pigs

Background:Preventing heterologous protein influx in patients is important when using xenogeneic bioartificial livers(BALs)to treat liver failure.The development of transgenic porcine livers synthesizing human proteins is a promising approach in this regard.Here,we evaluated the safety and efficacy of a transgenic porcine liver synthesizing human albumin(h ALB)and coagulation factor VII(h FVII)within a bioartificial system.Methods:Tibetan miniature pigs were randomly subjected to different interventions after surgeryinduced partially ischemic liver failure.Group A(n=4)was subjected to basic treatment;group B(n=4)was to standard medical treatment and wild-type porcine BAL perfusion,and group C(n=2)was to standard medical treatment and transgenic BAL perfusion.Biochemical parameters,coagulation status,survival time,and pathological changes were determined.Expressions of h ALB and h FVII were detected using immunohistochemistry and enzyme-linked immunosorbent assays.Results:The survival time in group A was 9.75±1.26 days;this was shorter than that in both perfused groups,in which all animals reached an endpoint of 12 days(P=0.006).Ammonia,bilirubin,and lactate levels were significantly decreased,whereas albumin and fibrinogen levels were increased after perfusion(all P<0.05).h ALB and h FVII were detected in transgenic BAL-perfused pig serum and ex vivo in the liver tissues.Conclusions:The humanized transgenic pig livers could synthesize and secrete h ALB and h FVII ex vivo in a whole organ-based bioartificial system,while maintaining their metabolism,detoxification,transformation,and excretion functions,which were comparable to those observed in wild-type porcine livers.Therefore,the use of transgenic bioartificial whole livers is expected to become a new approach in treating acute liver failure.

Essential oil extracted from Quzhou Aurantii Fructus prevents acute liver failure through inhibiting lipopolysaccharide-mediated inflammatory response

Quzhou Aurantii Fructus(QAF)has a long history as a folk medicine and food for the treatment of liver diseases.While our earlier study provided evidence of hepatoprotective properties contained within the flavonoids and limonins constituents in QAF,the potential preventative effects afforded by essential oil components present within QAF remains enigmatic.In this study,we prepared Quzhou Aurantii Fructus essential oil(QAFEO)and confirmed its anti-inflammatory effects on liver inflammation through experimentation on lipopolysaccharide and D-galactosamine(LPS/D-GalN)induced acute liver failure(ALF)mouse models.Using RNA-sequence(RNA-seq)analysis,we found that QAFEO prevented ALF by systematically blunting the pathways involved in response to LPS and toll-like receptor signaling pathways.QAFEO effectively suppressed the phosphorylation of tank-binding kinase 1(TBK1),TGF-beta activated kinase 1(TAK1),interferon regulatory factor 3(IRF3),and the activation of mitogen activated kinase-like protein(MAPK)and nuclear factor-kappa B(NF-κB)pathways in vivo and in vitro.Importantly,QAFEO substantially reduced myeloid differentiation primary response gene 88(MyD88)-toll-like receptor 4(TLR4)interaction levels.Moreover,8 compounds from QAFEO could directly bind to REAL,TAK1,MyD88,TBK1,and IRF3.Taken together,the results of our study support the notion that QAFEO exerts a hepatoprotective effect through inhibiting LPS-mediated inflammatory response.

Astragaloside IV Ameliorates Inflammatory Damage in Mice with Acute Liver Failure

Acute liver failure is a life-threatening clinical syndrome with a high mortality rate. Currently, the research on Astragaloside IV in liver diseases primarily focuses on liver cancer, and there is limited understanding of its mechanism in acute liver failure’s innate immunity. Therefore, this study aims to investigate the potential protective effect of Astragaloside IV on acute liver failure and its impact on innate immune cells. The study employed D-GalN/LPS-induced acute liver failure mouse models and employed various techniques such as a range of molecular and analytical techniques. The experimental results demonstrated that treatment with Astragaloside IV significantly reduced the inflammatory response, alleviated liver injury, and improved the survival rate of mice with acute liver failure induced by D-GalN/LPS. Further investigations revealed that AS-IV played a beneficial role by regulating the proportion of CD11b+Ly6Chi monocytes and the secretion of inflammatory cytokines and anti-inflammatory metabolites. These findings suggest that the pharmacological mechanism of AS-IV may involve targeted regulation of CD11b+Ly6Chi monocytes in both peripheral blood and liver. The implications of this study’s results are twofold. Firstly, they provide a basis for the clinical application of AS-IV in treating liver failure, offering potential therapeutic benefits. Secondly, they serve as a reference for further development of safer and more effective modified compounds.

Ercao Qinggan decoction regulates apoptosis of hepatocytes in mice with acute liver failure via the TLR4-mediated PI3K/Akt/GSK3βsignal pathway

Background:To clarify the inhibitory effect of Ercao Qinggan decoction(EQD)on acute liver failure(ALF)and its related mechanisms.Methods:HL-7702 hepatocytes were pretreated with TLR4 inhibitor CLI-095,glycogen synthase kinase 3β(GSK3β)inhibitor LiCl and different doses of EQD for 2 hours,and lipopolysaccharide(LPS)(10μg/mL)for 24 hours.Cell apoptosis,TNF-αand IL-6 and GSK3βwere detected by flow cytometry,immunofluorescence,quantitative polymerase chain reaction.After mice were gavaged with different concentrations of EQD for 12 days,ALF mouse models were established intraperitoneal injection of D-Gal/LPS.After 24 hours,the mice were euthanized and the liver tissue was stained with hematoxylin and eosin.Liver cell apoptosis,the serum levels of aspartate aminotransferase,alanine aminotransferase,TNF-αand IL-βwere detected by terminal transferase-mediated dUTP nick end-labelling,enzyme linked immunosorbent assay,quantitative polymerase chain reaction,and Western blotting,respectively.These methods were also used to test the mRNA expression of Bax,Bcl-2 and the protein expression of GSK3β,p-Akt/Akt in livers.Results:CLI-095,LiCl,and EQD significantly inhibited apoptosis induced by LPS,the mRNA expression of IL-6,TNF-αand the nuclear translocation of GSK3βin HL-7702 hepatocytes.EQD dose-dependently inhibited hepatocyte apoptosis,the serum concentration of aspartate aminotransferase and ALT,the expression of TNF-αand IL-β,the ratio of p-GSK3β/GSK3β,p-Akt/Akt in alanine aminotransferase mice.Conclusion:EQD can inhibit hepatocyte apoptosis in ALF mice through regulating TLR4/PI3K/Akt/GSK3βsignaling pathway.

Intracranial pressure monitoring in the perioperative period of patients with acute liver failure undergoing orthotopic liver transplantation

Acute liver failure(ALF)may result in severe neurological complications caused by cerebral edema and elevated intracranial pressure(ICP).Multiple pathogenic mechanisms explain the elevated ICP,and newer hypotheses have been described.While invasive ICP monitoring(ICPM)may have a role in ALF management,these patients are typically coagulopathic and at risk for intracranial hemorrhage.ICPM is the subject of much debate,and significant heterogeneity exists in clinical practice regarding its use.Contemporary ICPM techniques and coagulopathy reversal strategies may be associated with a lower risk of hemor-rhage;however,most of the evidence is limited by its retrospective nature and relatively small sample size.

Indocyanine green clearance test combined with MELD score in predicting the short-term prognosis of patients with acute liver failure

BACKGROUND: Acute liver failure(ALF) is an acute severe deterioration of liver function with high mortality. Early and accurate prognostic assessment of patients with ALF is critically important. Although the model for end-stage liver disease(MELD) scores and King’s College Hospital(KCH) criteria are well-accepted as predictive tools, their accuracy is unsatisfactory.The indocyanine green(ICG) clearance test(ICGR15, ICG retention rate at the 15 minutes) is a sensitive indicator of liver function. In this study, we investigated the efficacy of the ICGR15 for the short-term prognosis in patients with ALF. We compared the predictive value of ICGR15 with the MELD scores and KCH criteria.METHODS: Sixty-nine patients who had been diagnosed with ALF were recruited retrospectively. ICGR15 had been performed by ICG pulse spectrophotometry and relevant clinical and laboratory indices were analyzed within 24 hours of diagnosis.In addition, the MELD scores and KCH criteria were calculated.RESULTS: The three-month mortality of all patients was 47.83%.Age, serum total bilirubin and creatinine concentrations,international normalized ratio for prothrombin time, ICGR15,MELD scores and KCH criteria differed significantly between surviving and deceased patients. A positive correlation was observed between ICGR15 and MELD scores(r=0.328, P=0.006).The ICGR15-MELD model, Logit(P)=0.096×ICGR15+0.174 ×MELD score–9.346, was constructed by logistic regression analysis. The area under the receiver operating characteristic curve was 0.855. When set the cut-off point to-0.4684, the sensitivity was 87.90% and specificity, 72.20%. The area under the receiver operating characteristic curve of the ICGR15-MELD model(0.855) was significantly higher than that of the ICGR15(0.793), MELD scores(0.776) and KCH criteria(0.659).Based on this cut-off value, the patients were divided into two groups. The mortality was 74.36% in the first group(ICGR15-MELD≥-0.4686) and 13.33% in the second group(ICGR15-MELD<-0.4686), with a significant difference between the two groups(χ2=25.307, P=0.000).CONCLUSION: The ICGR15-MELD model is superior to the ICGR15, MELD scores, and KCH criteria in predicting the shortterm prognosis of patients with ALF.

Diagnostic criteria for acute liver failure due to Wilson disease

AIM： To describe the diagnostic criteria for acute liver failure due to Wilson disease （WD）, which is an uncommon cause of acute liver failure （ALF）. METHODS： We compared findings of patients presenting with ALF due to WD to those with ALF of other etiologies. RESULTS： Previously described criteria, such as low alkaline phosphatase activity, ratio of low alkaline phosphatase to total bilirubin or ratio of high aspartate arninotransferase （AST） to alanine arninotransferase （ALT）, failed to identify patients with ALF due to WD. There were significant differences in low ALT and AST activities （53 ± 43 vs 1982 ± 938, P 〈 0.0001 and 87 ± 44 vs 2756 ± 2941, P = 0.037, respectively）, low choline esterase activity （1.79 ± 1.2 vs 4.30 ± 1.2, P = 0.009）, high urine copper concentrations （93.4 ± 144.0 vs 3.5 ± 1.8, P = 0.001） and low hemoglobin （7.0 ± 2.2 vs 12.6 ± 1.8, P 〈 0.0001） in patients with ALF caused by WD as compared with other etiologies. Interestingly, 4 of 7 patients with ALF due to WD survived without liver transplantation. CONCLUSION： In ALF, these criteria can help establish a diagnosis of WD. Where applicable, slitlamp examination for presence of Kayser-Fleischer rings and liver biopsy for determination of hepatic copper concentration still remain important for the diagnosis of ALF due to WD. The need for liver transplantation should be evaluated carefully as the prognosis is not necessarily fatal.

Prognostic models for acute liver failure

BACKGROUND: Acute liver failure (ALF) remains a dramatic and unpredictable disease with high morbidity and mortality. Early and accurate prognostic assessment of patients with ALF is critically important for optimum clinical pathway. DATA SOURCES: Five English-language medical databases, MEDLINE, Science Direct, OVID, Springer Link and Wiley Interscience were searched for articles on 'acute liver failure', 'prognosis', and related topics. RESULTS: Multi-variable prognostic models including the King's College Hospital criteria and the model for end-stage liver disease score have been widely used in determination of the prognosis of ALF, but the results are far from satisfactory. Other prognostic indicators including serum Gc-globulin, arterial blood lactate, serum phosphate, arterial blood ammonia, and serum alpha-fetoprotein are promising but await further assessement. CONCLUSIONS: A reliable prognostic model to be developed in the future should not only have predictive value for poor outcome but also help to predict the survival of patients without a liver transplantation. Further studies are necessary to assess the prognostic accuracy of any new models. (Hepatobiliary Pancreat Dis Int 2010; 9: 122-128)