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 ...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.展开更多
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 ...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.展开更多
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 in...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.展开更多
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 rar...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.展开更多
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 ...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.展开更多
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...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.展开更多
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.Pedi...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.展开更多
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 protein...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.展开更多
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 ...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.展开更多
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 understandi...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<sup>+</sup>Ly6C<sup>hi</sup> 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<sup>+</sup>Ly6C<sup>hi</sup> 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.展开更多
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 synthas...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.展开更多
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 hav...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.展开更多
Acute liver failure (ALF) is a devastating clinical syndrome characterised by progressive encephalopathy, coagulopathy, and circulatory dysfunction, which commonly leads to multiorgan failure and death. Central to the...Acute liver failure (ALF) is a devastating clinical syndrome characterised by progressive encephalopathy, coagulopathy, and circulatory dysfunction, which commonly leads to multiorgan failure and death. Central to the pathogenesis of ALF is activation of the immune system with mobilisation of cellular effectors and massive production of cytokines. As key components of the innate immune system, monocytes and macrophages are postulated to play a central role in the initiation, progression and resolution of ALF. ALF in humans follows a rapidly progressive clinical course that poses inherent difficulties in delineating the role of these pivotal immune cells. Therefore, a number of experimental models have been used to study the pathogenesis of ALF. Here we consider the evidence from experimental and human studies of ALF on the role of monocytes and macrophages in acute hepatic injury and the ensuing extrahepatic manifestations, including functional monocyte deactivation and multiple organ failure.展开更多
BACKGROUND: Transplantation of mesenchymal stem cells(MSCs) has been regarded as a potential treatment for acute liver failure(ALF), but the optimal route was unknown. The present study aimed to explore the most effec...BACKGROUND: Transplantation of mesenchymal stem cells(MSCs) has been regarded as a potential treatment for acute liver failure(ALF), but the optimal route was unknown. The present study aimed to explore the most effective MSCs transplantation route in a swine ALF model.METHODS: The swine ALF model induced by intravenous injection of D-Gal was treated by the transplantation of swine MSCs through four routes including intraportal injection(In P group), hepatic intra-arterial injection(AH group), peripheral intravenous injection(PV group) and intrahepatic injection(IH group). The living conditions and survival time were recorded. Blood samples before and after MSCs transplantation were collected for the analysis of hepatic function. The histology of liver injury was interpreted and scored in terminal samples. Hepatic apoptosis was detected by TUNEL assay. Apoptosis and proliferation related protein expressions including cleaved caspase-3, survivin, AKT, phospho-AKT(Ser473), ERK and phospho-ERK(Tyr204) were analyzed by Western blotting.RESULTS: The average survival time of each group was 10.7 ±1.6 days(In P), 6.0±0.9 days(AH), 4.7±1.4 days(PV), 4.3±0.8 days(IH), respectively, when compared with the average survival time of 3.8±0.8 days in the D-Gal group. The survival rates between the In P group and D-Gal group revealed a statistically significant difference(P<0.01). Pathological and biochemical analysis showed that liver damage was the worst in the D-Gal group, while less injury in the In P group. Histopathological scores revealed a significant decrease in the In P group(3.17±1.04, P<0.01) and AH group(8.17±0.76, P<0.05) as compared with that in the D-Gal group(11.50±1.32). The apoptosis rate in the In P group(25.0%±3.4%, P<0.01) and AH group(40.5%±1.0%, P<0.05) was lower than that in the D-Gal group(70.6%±8.5%). The expression of active caspase-3 was inhibited, while the expression of survivin, AKT, phosphoAKT(Ser473), ERK and phospho-ERK(Tyr204) was elevated in the In P group.CONCLUSIONS: Intraportal injection was superior to other pathways for MSC transplantation. Intraportal MSC transplantation could improve liver function, inhibit apoptosis and prolong the survival time of swine with ALF. The transplanted MSCs may participate in liver regeneration via promoting cell proliferation and suppressing apoptosis during the initial stage of ALF.展开更多
BACKGROUND:Acute liver failure(ALF) caused by viral and non-viral hepatitis is often accompanied with severe metabolic disorders,the accumulation of toxic substances and continuous release and accumulation of a large ...BACKGROUND:Acute liver failure(ALF) caused by viral and non-viral hepatitis is often accompanied with severe metabolic disorders,the accumulation of toxic substances and continuous release and accumulation of a large number of endogenous toxins and inflammatory mediators. The present study aimed to investigate the effects of various combined non-biological artif icial liver treatments for patients with acute liver failure(ALF) complicated by multiple organ dysfunction syndrome(MODS).METHODS:Thirty-one patients with mid- or late-stage liver failure complicated by MODS(score 4) were randomly divided into three treatment groups:plasmapheresis(PE) combined with hemoperfusion(HP) and continuous venovenous hemodiafiltration(CVVHDF),PE+CVVHDF,and HP+CVVHDF,respectively. Heart rate(HR) before and after treatment,mean arterial pressure(MAP),respiratory index(PaO2/FiO2),hepatic function,platelet count,and blood coagulation were determined.RESULTS:Signifi cant improvement was observed in HR,MAP,PaO2/FiO2,total bilirubin(TBIL) and alanine aminotransferase(ALT) levels after treatment(P<0.05). TBIL and ALT decreased more signifi cantly after treatment in the PE+CVVHDF and PE+HP+CVVHDF groups(P<0.01). Prothrombin time(PT) and albumin were signifi cantly improved only in the PE+CVVHDF and PE+HP+CVVHDF groups(P<0.05). TBIL decreased more significantly in the PE+HP+CVVHDF group than in the HP+CVVHDF and PE+CVVHDF groups(P<0.05). The survival rate of the patients was 58.1%(18/31),viral survival rate 36.4%(4/11),and non-viral survival rate 70%(14/20).CONCLUSION:Liver function was relatively improved after treatment,but PE+HP+CVVHDF was more efficient for the removal of toxic metabolites,especially bilirubin. The survival rate was signifi cantly higher in the patients with non-viral liver failure than in those with viral liver failure.展开更多
BACKGROUND Acute liver failure(ALF)can be a primary presentation of Wilson disease(WD).Mortality rates are high in WD with ALF(WDALF).Predictions of mortality in WDALF vary by model and are sometimes contradictory,per...BACKGROUND Acute liver failure(ALF)can be a primary presentation of Wilson disease(WD).Mortality rates are high in WD with ALF(WDALF).Predictions of mortality in WDALF vary by model and are sometimes contradictory,perhaps because few patients are studied or WD diagnoses are questionable.AIM To determine the outcomes among well-documented WDALF patients and assess mortality model performance in this cohort.METHODS We reviewed the medical records of our pediatric WDALF patients(n=41 over 6-years-old,single-center retrospective study)and compared seven prognostic models(King’s College Hospital Criteria,model for end-stage liver disease/pediatric end-stage liver disease scoring systems,Liver Injury Unit[LIU]using prothrombin time[PT]or international normalized ratio[INR],admission LIU using PT or INR,and Devarbhavi model)with one another.RESULTS Among the 41 Han Chinese patients with ALF,WD was established by demonstrating ATP7B variants in 36.In 5 others,Kayser-Fleischer rings and Coombs-negative hemolytic anemia permitted diagnosis.Three died during hospitalization and three underwent liver transplantation(LT)within 1 mo of presentation and survived(7.3%each);35(85.4%)survived without LT when given enteral D-penicillamine and zinc-salt therapy with or without urgent plasmapheresis.Parameters significantly correlated with mortality included encephalopathy,coagulopathy,and gamma-glutamyl transpeptidase activity,bilirubin,ammonia,and serum sodium levels.Area under the receiver operating curves varied among seven prognostic models from 0.981 to 0.748 with positive predictive values from 0.214 to 0.429.CONCLUSION WDALF children can survive and recover without LT when given D-penicillamine and Zn with or without plasmapheresis,even after enlisting for LT.展开更多
AIM To establish a simplified, reproducible D-galactosamineinduced cynomolgus monkey model of acute liver failure having an appropriate treatment window. METHODS Sixteen cynomolgus monkeys were randomly dividedinto fo...AIM To establish a simplified, reproducible D-galactosamineinduced cynomolgus monkey model of acute liver failure having an appropriate treatment window. METHODS Sixteen cynomolgus monkeys were randomly dividedinto four groups(A, B, C and D) after intracranial pressure(ICP) sensor implantation. D-galactosamine at 0.3, 0.25, 0.20 + 0.05(24 h interval), and 0.20 g/kg body weight, respectively, was injected via the small saphenous vein. Vital signs, ICP, biochemical indices, and inflammatory factors were recorded at 0, 12, 24, 36, 48, 72, 96, and 120 h after D-galactosamine administration. Progression of clinical manifestations, survival times, and results of H&E staining, TUNEL, and Masson staining were recorded. RESULTS Cynomolgus monkeys developed different degrees of debilitation, loss of appetite, and jaundice after D-galactosamine administration. Survival times of groups A, B, and C were 56 ± 8.7 h, 95 ± 5.5 h, and 99 ± 2.2 h, respectively, and in group D all monkeys survived the 144-h observation period except for one, which died at 136 h. Blood levels of ALT, AST, CK, LDH, TBi L, Cr, BUN, and ammonia, prothrombin time, ICP, endotoxin, and inflammatory markers [(tumor necrosis factor(TNF)-α, interleukin(IL)-1β, and IL-6)] significantly increased compared with baseline values in different groups(P < 0.05). Pathological results showed obvious liver cell necrosis that was positively correlated with the dose of D-galactosamine.CONCLUSION We successfully established a simplified, reproducible D-galactosamine-induced cynomolgus monkey model of acute liver failure, and the single or divided dosage of 0.25 g/kg is optimal for creating this model.展开更多
Acute liver failure(ALF),a fatal clinical disease featured with overwhelming hepatocyte necrosis,is a grand challenge in global health.However,a satisfactory therapeutic option for curing ALF is still absent,other tha...Acute liver failure(ALF),a fatal clinical disease featured with overwhelming hepatocyte necrosis,is a grand challenge in global health.However,a satisfactory therapeutic option for curing ALF is still absent,other than liver transplantation.Nanobiomaterials are currently being developed for the diagnosis and treatment of ALF.The liver can sequester most of nanoparticles from blood circulation,which becomes an intrinsic superiority for nanobiomaterials targeting hepatic diseases.Nanobiomaterials can enhance the bioavailability of free drugs,thereby significantly improving the therapeutic effects in ALF.Nanobiomaterials can also increase the liver accumulation of therapeutic agents and enable more effective targeting of the liver or specific liver cells.In addition,stimuli-responsive,optical,or magnetic nanomaterials exhibit great potential in the therapeutical,diagnostic,and imaging applications in ALF.Therefore,therapeutic agents in combination with nanobiomaterials increase the specificity of ALF therapy,diminish adverse systemic effects,and offer a multifunctional theranostic platform.Nanobiomaterial holds excellent significance and prospects in ALF theranostics.In this review,we summarize the therapeutic mechanisms and targeting strategies of various nanobiomaterials in ALF.We highlight recent developments of diverse nanomedicines for ALF therapy,diagnosis,and imaging.Furthermore,the challenges and future perspectives in the theranostics of ALF are also discussed.展开更多
Drug-induced liver injury(DILI),which refers to liver damage caused by a drug or its metabolites,has emerged as an important cause of acute liver failure(ALF)in recent years.Chemically-induced ALF in animal models mim...Drug-induced liver injury(DILI),which refers to liver damage caused by a drug or its metabolites,has emerged as an important cause of acute liver failure(ALF)in recent years.Chemically-induced ALF in animal models mimics the pathology of DILI in humans;thus,these models are used to study the mechanism of potentially effective treatment strategies.Mesenchymal stromal cells(MSCs)possess immunomodulatory properties,and they alleviate acute liver injury and decrease the mortality of animals with chemically-induced ALF.Here,we summarize some of the existing research on the interaction between MSCs and immune cells,and discuss the possible mechanisms underlying the immunomodulatory activity of MSCs in chemically-induced ALF.We conclude that MSCs can impact the phenotype and function of macrophages,as well as the differentiation and maturation of dendritic cells,and inhibit the proliferation and activation of T lymphocytes or B lymphocytes.MSCs also have immunomodulatory effects on the production of cytokines,such as prostaglandin E2 and tumor necrosis factor-alpha-stimulated gene 6,in animal models.Thus,MSCs have significant benefits in the treatment of chemically-induced ALF by interacting with immune cells and they may be applied to DILI in humans in the near future.展开更多
Acute liver failure(ALF)has an abrupt onset with a frequently fatal outcome.Previous studies have found that oral antibiotics prevent drug-induced liver injury in animal experiments,indicating that the gut microbiota ...Acute liver failure(ALF)has an abrupt onset with a frequently fatal outcome.Previous studies have found that oral antibiotics prevent drug-induced liver injury in animal experiments,indicating that the gut microbiota plays a critical role in the pathophysiological process.However,the underlying mechanism has not been fully understood.This study explored the comprehensive role of the gut microbiota in ALF using multi-omics.A cocktail of broad-spectrum antibiotics(Abx)pretreatment by gavage for four weeks improved the survival of D-(+)-galactosamine hydrochloride(D-Gal)/lipopolysaccharide(LPS)-induced ALF in C57BL/6 mice.RNA sequencing showed that inflammatory responses were inhibited and metabolic pathways were upregulated in the liver of Abx-treated ALF mice.The 16S rRNA gene sequencing revealed that Abx reshaped the composition and function of the gut microbiota,with an increased proportion of tryptophan(Trp)metabolism.In addition,global metabolic profiling by ultraperformance liquid chromatography–mass spectrometry(UPLC–MS)indicated that the gut microbiota post-Abx intervention reduced Trp excretion,liberated more Trp to the host,and enhanced the kynurenine(Kyn)pathway with increased production of Kyn.As an endogenous aryl hydrocarbon receptor(AhR)ligand,Kyn has anti-inflammatory and immunosuppressive effects.Furthermore,AhR-targeted treatments affected the outcome of ALF mice with or without Abx pretreatment,indicating that AhR directly regulated susceptibility to ALF,at least in part.This study demonstrates that the gut microbiota-dependent control of the Trp metabolism could regulate host susceptibility to ALF by modulating the activity of AhR,and thus provides a promising target for better management of ALF.展开更多
基金supported by the grant from the National Natural Science Foundation of China (82070609)
文摘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.
文摘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.
基金reviewed and approved by the Ethics Committee of the First People’s Hospital of Lianyungang,No.LW-20231120001-01.
文摘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.
文摘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.
基金the National Natural Science Foundation of China,No.82100630 and No.82100894the Fundamental Research Funds for the Central Universities,No.2042021kf0080.
文摘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.
基金This project was supported by grants from the National Science and Technology Major Project(No.2014ZX10005001 and No.2018ZX10302204-001)Chen Xiaoping Development Foundation(No.CXPJJH12000002-2020032).
文摘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.
文摘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.
基金supported by grants from the National Key R&D Program of China(2018YFC1106400 and 2018YFA0108200)the National Natural Science Foundation of China(31972926)+3 种基金the Natural Science Foundation of Guangdong Province(2014A030312013 and 2018A030313128)Guangdong Key Research and Development Plan(2019B020234003)Science and Technology Program of Guangzhou(201803010086)Guangdong Basic and Applied Basic Research Foundation(2020A1515111111)。
文摘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.
文摘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.
文摘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<sup>+</sup>Ly6C<sup>hi</sup> 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<sup>+</sup>Ly6C<sup>hi</sup> 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.
基金The National Natural Science Foundation of Zhejiang Provincial(No.LGF21H270001)the Association of Integrated Chinese and Western Medicine Research Fund Project of Zhejiang Provincial(No.2019LY013)the Basic Research Project of Wenzhou Science and Technology Bureau(No.Y20210149)supported this study.
文摘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.
文摘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.
文摘Acute liver failure (ALF) is a devastating clinical syndrome characterised by progressive encephalopathy, coagulopathy, and circulatory dysfunction, which commonly leads to multiorgan failure and death. Central to the pathogenesis of ALF is activation of the immune system with mobilisation of cellular effectors and massive production of cytokines. As key components of the innate immune system, monocytes and macrophages are postulated to play a central role in the initiation, progression and resolution of ALF. ALF in humans follows a rapidly progressive clinical course that poses inherent difficulties in delineating the role of these pivotal immune cells. Therefore, a number of experimental models have been used to study the pathogenesis of ALF. Here we consider the evidence from experimental and human studies of ALF on the role of monocytes and macrophages in acute hepatic injury and the ensuing extrahepatic manifestations, including functional monocyte deactivation and multiple organ failure.
基金supported by grants from the National Natural Science Foundation of China(81300338)863 National Science and Technology Plans(2013AA020102)Project Funding of Clinical Medical Center of Digestive Disease in Jiangsu Province(BL2012001)
文摘BACKGROUND: Transplantation of mesenchymal stem cells(MSCs) has been regarded as a potential treatment for acute liver failure(ALF), but the optimal route was unknown. The present study aimed to explore the most effective MSCs transplantation route in a swine ALF model.METHODS: The swine ALF model induced by intravenous injection of D-Gal was treated by the transplantation of swine MSCs through four routes including intraportal injection(In P group), hepatic intra-arterial injection(AH group), peripheral intravenous injection(PV group) and intrahepatic injection(IH group). The living conditions and survival time were recorded. Blood samples before and after MSCs transplantation were collected for the analysis of hepatic function. The histology of liver injury was interpreted and scored in terminal samples. Hepatic apoptosis was detected by TUNEL assay. Apoptosis and proliferation related protein expressions including cleaved caspase-3, survivin, AKT, phospho-AKT(Ser473), ERK and phospho-ERK(Tyr204) were analyzed by Western blotting.RESULTS: The average survival time of each group was 10.7 ±1.6 days(In P), 6.0±0.9 days(AH), 4.7±1.4 days(PV), 4.3±0.8 days(IH), respectively, when compared with the average survival time of 3.8±0.8 days in the D-Gal group. The survival rates between the In P group and D-Gal group revealed a statistically significant difference(P<0.01). Pathological and biochemical analysis showed that liver damage was the worst in the D-Gal group, while less injury in the In P group. Histopathological scores revealed a significant decrease in the In P group(3.17±1.04, P<0.01) and AH group(8.17±0.76, P<0.05) as compared with that in the D-Gal group(11.50±1.32). The apoptosis rate in the In P group(25.0%±3.4%, P<0.01) and AH group(40.5%±1.0%, P<0.05) was lower than that in the D-Gal group(70.6%±8.5%). The expression of active caspase-3 was inhibited, while the expression of survivin, AKT, phosphoAKT(Ser473), ERK and phospho-ERK(Tyr204) was elevated in the In P group.CONCLUSIONS: Intraportal injection was superior to other pathways for MSC transplantation. Intraportal MSC transplantation could improve liver function, inhibit apoptosis and prolong the survival time of swine with ALF. The transplanted MSCs may participate in liver regeneration via promoting cell proliferation and suppressing apoptosis during the initial stage of ALF.
基金supported by a grant from Xuzhou Municipal,China
文摘BACKGROUND:Acute liver failure(ALF) caused by viral and non-viral hepatitis is often accompanied with severe metabolic disorders,the accumulation of toxic substances and continuous release and accumulation of a large number of endogenous toxins and inflammatory mediators. The present study aimed to investigate the effects of various combined non-biological artif icial liver treatments for patients with acute liver failure(ALF) complicated by multiple organ dysfunction syndrome(MODS).METHODS:Thirty-one patients with mid- or late-stage liver failure complicated by MODS(score 4) were randomly divided into three treatment groups:plasmapheresis(PE) combined with hemoperfusion(HP) and continuous venovenous hemodiafiltration(CVVHDF),PE+CVVHDF,and HP+CVVHDF,respectively. Heart rate(HR) before and after treatment,mean arterial pressure(MAP),respiratory index(PaO2/FiO2),hepatic function,platelet count,and blood coagulation were determined.RESULTS:Signifi cant improvement was observed in HR,MAP,PaO2/FiO2,total bilirubin(TBIL) and alanine aminotransferase(ALT) levels after treatment(P<0.05). TBIL and ALT decreased more signifi cantly after treatment in the PE+CVVHDF and PE+HP+CVVHDF groups(P<0.01). Prothrombin time(PT) and albumin were signifi cantly improved only in the PE+CVVHDF and PE+HP+CVVHDF groups(P<0.05). TBIL decreased more significantly in the PE+HP+CVVHDF group than in the HP+CVVHDF and PE+CVVHDF groups(P<0.05). The survival rate of the patients was 58.1%(18/31),viral survival rate 36.4%(4/11),and non-viral survival rate 70%(14/20).CONCLUSION:Liver function was relatively improved after treatment,but PE+HP+CVVHDF was more efficient for the removal of toxic metabolites,especially bilirubin. The survival rate was signifi cantly higher in the patients with non-viral liver failure than in those with viral liver failure.
文摘BACKGROUND Acute liver failure(ALF)can be a primary presentation of Wilson disease(WD).Mortality rates are high in WD with ALF(WDALF).Predictions of mortality in WDALF vary by model and are sometimes contradictory,perhaps because few patients are studied or WD diagnoses are questionable.AIM To determine the outcomes among well-documented WDALF patients and assess mortality model performance in this cohort.METHODS We reviewed the medical records of our pediatric WDALF patients(n=41 over 6-years-old,single-center retrospective study)and compared seven prognostic models(King’s College Hospital Criteria,model for end-stage liver disease/pediatric end-stage liver disease scoring systems,Liver Injury Unit[LIU]using prothrombin time[PT]or international normalized ratio[INR],admission LIU using PT or INR,and Devarbhavi model)with one another.RESULTS Among the 41 Han Chinese patients with ALF,WD was established by demonstrating ATP7B variants in 36.In 5 others,Kayser-Fleischer rings and Coombs-negative hemolytic anemia permitted diagnosis.Three died during hospitalization and three underwent liver transplantation(LT)within 1 mo of presentation and survived(7.3%each);35(85.4%)survived without LT when given enteral D-penicillamine and zinc-salt therapy with or without urgent plasmapheresis.Parameters significantly correlated with mortality included encephalopathy,coagulopathy,and gamma-glutamyl transpeptidase activity,bilirubin,ammonia,and serum sodium levels.Area under the receiver operating curves varied among seven prognostic models from 0.981 to 0.748 with positive predictive values from 0.214 to 0.429.CONCLUSION WDALF children can survive and recover without LT when given D-penicillamine and Zn with or without plasmapheresis,even after enlisting for LT.
基金Supported by The National Natural Science Foundation of China,No.81470875The Natural Science Foundation of Guangdong Province,China,No.2014A030312013+1 种基金The Science and Technology Planning Project of Guangdong Province,China,No.2014B020227002,No.2015B090903069,and No.2015B020229002The Science and Technology Program of Guangzhou,China,No.201604020002
文摘AIM To establish a simplified, reproducible D-galactosamineinduced cynomolgus monkey model of acute liver failure having an appropriate treatment window. METHODS Sixteen cynomolgus monkeys were randomly dividedinto four groups(A, B, C and D) after intracranial pressure(ICP) sensor implantation. D-galactosamine at 0.3, 0.25, 0.20 + 0.05(24 h interval), and 0.20 g/kg body weight, respectively, was injected via the small saphenous vein. Vital signs, ICP, biochemical indices, and inflammatory factors were recorded at 0, 12, 24, 36, 48, 72, 96, and 120 h after D-galactosamine administration. Progression of clinical manifestations, survival times, and results of H&E staining, TUNEL, and Masson staining were recorded. RESULTS Cynomolgus monkeys developed different degrees of debilitation, loss of appetite, and jaundice after D-galactosamine administration. Survival times of groups A, B, and C were 56 ± 8.7 h, 95 ± 5.5 h, and 99 ± 2.2 h, respectively, and in group D all monkeys survived the 144-h observation period except for one, which died at 136 h. Blood levels of ALT, AST, CK, LDH, TBi L, Cr, BUN, and ammonia, prothrombin time, ICP, endotoxin, and inflammatory markers [(tumor necrosis factor(TNF)-α, interleukin(IL)-1β, and IL-6)] significantly increased compared with baseline values in different groups(P < 0.05). Pathological results showed obvious liver cell necrosis that was positively correlated with the dose of D-galactosamine.CONCLUSION We successfully established a simplified, reproducible D-galactosamine-induced cynomolgus monkey model of acute liver failure, and the single or divided dosage of 0.25 g/kg is optimal for creating this model.
基金supported by the National Key Research and Development Program of China(2019YFA0111300)the National Natural Science Foundation of China(21907113,51903256,32001012)the Guangdong Province Science and Technology Innovation Special Fund(International Scientific Cooperation,2018A050506035).
文摘Acute liver failure(ALF),a fatal clinical disease featured with overwhelming hepatocyte necrosis,is a grand challenge in global health.However,a satisfactory therapeutic option for curing ALF is still absent,other than liver transplantation.Nanobiomaterials are currently being developed for the diagnosis and treatment of ALF.The liver can sequester most of nanoparticles from blood circulation,which becomes an intrinsic superiority for nanobiomaterials targeting hepatic diseases.Nanobiomaterials can enhance the bioavailability of free drugs,thereby significantly improving the therapeutic effects in ALF.Nanobiomaterials can also increase the liver accumulation of therapeutic agents and enable more effective targeting of the liver or specific liver cells.In addition,stimuli-responsive,optical,or magnetic nanomaterials exhibit great potential in the therapeutical,diagnostic,and imaging applications in ALF.Therefore,therapeutic agents in combination with nanobiomaterials increase the specificity of ALF therapy,diminish adverse systemic effects,and offer a multifunctional theranostic platform.Nanobiomaterial holds excellent significance and prospects in ALF theranostics.In this review,we summarize the therapeutic mechanisms and targeting strategies of various nanobiomaterials in ALF.We highlight recent developments of diverse nanomedicines for ALF therapy,diagnosis,and imaging.Furthermore,the challenges and future perspectives in the theranostics of ALF are also discussed.
基金National Natural Science Foundation of China,No.81971756and Stem Cell and Translational Research from National Key Research and Development Program of China,No.2016YFA0101001.
文摘Drug-induced liver injury(DILI),which refers to liver damage caused by a drug or its metabolites,has emerged as an important cause of acute liver failure(ALF)in recent years.Chemically-induced ALF in animal models mimics the pathology of DILI in humans;thus,these models are used to study the mechanism of potentially effective treatment strategies.Mesenchymal stromal cells(MSCs)possess immunomodulatory properties,and they alleviate acute liver injury and decrease the mortality of animals with chemically-induced ALF.Here,we summarize some of the existing research on the interaction between MSCs and immune cells,and discuss the possible mechanisms underlying the immunomodulatory activity of MSCs in chemically-induced ALF.We conclude that MSCs can impact the phenotype and function of macrophages,as well as the differentiation and maturation of dendritic cells,and inhibit the proliferation and activation of T lymphocytes or B lymphocytes.MSCs also have immunomodulatory effects on the production of cytokines,such as prostaglandin E2 and tumor necrosis factor-alpha-stimulated gene 6,in animal models.Thus,MSCs have significant benefits in the treatment of chemically-induced ALF by interacting with immune cells and they may be applied to DILI in humans in the near future.
基金the Major Program of the National Natural Science Foundation of China(81790630 and 81790633)the Sino-German Center for Research Promotion(GZ1546)the Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(2019-I2M-5-045).
文摘Acute liver failure(ALF)has an abrupt onset with a frequently fatal outcome.Previous studies have found that oral antibiotics prevent drug-induced liver injury in animal experiments,indicating that the gut microbiota plays a critical role in the pathophysiological process.However,the underlying mechanism has not been fully understood.This study explored the comprehensive role of the gut microbiota in ALF using multi-omics.A cocktail of broad-spectrum antibiotics(Abx)pretreatment by gavage for four weeks improved the survival of D-(+)-galactosamine hydrochloride(D-Gal)/lipopolysaccharide(LPS)-induced ALF in C57BL/6 mice.RNA sequencing showed that inflammatory responses were inhibited and metabolic pathways were upregulated in the liver of Abx-treated ALF mice.The 16S rRNA gene sequencing revealed that Abx reshaped the composition and function of the gut microbiota,with an increased proportion of tryptophan(Trp)metabolism.In addition,global metabolic profiling by ultraperformance liquid chromatography–mass spectrometry(UPLC–MS)indicated that the gut microbiota post-Abx intervention reduced Trp excretion,liberated more Trp to the host,and enhanced the kynurenine(Kyn)pathway with increased production of Kyn.As an endogenous aryl hydrocarbon receptor(AhR)ligand,Kyn has anti-inflammatory and immunosuppressive effects.Furthermore,AhR-targeted treatments affected the outcome of ALF mice with or without Abx pretreatment,indicating that AhR directly regulated susceptibility to ALF,at least in part.This study demonstrates that the gut microbiota-dependent control of the Trp metabolism could regulate host susceptibility to ALF by modulating the activity of AhR,and thus provides a promising target for better management of ALF.
