Evaluation of G3BP1 in the prognosis of acute and acute-on-chronic liver failure after the treatment of artificial liver support system

BACKGROUND The increased expression of G3BP1 was positively correlated with the prognosis of liver failure.AIM To investigate the effect of G3BP1 on the prognosis of acute liver failure(ALF)and acute-on-chronic liver failure(ACLF)after the treatment of artificial liver support system(ALSS).METHODS A total of 244 patients with ALF and ACLF were enrolled in this study.The levels of G3BP1 on admission and at discharge were detected.The validation set of 514 patients was collected to verify the predicted effect of G3BP1 and the viability of prognosis.RESULTS This study was shown that lactate dehydrogenase(LDH),alpha-fetoprotein(AFP)and prothrombin time were closely related to the prognosis of patients.After the ALSS treatment,the patient’amount of decreased G3BP1 index in difference of G3BP1 between the value of discharge and admission(difG3BP1)<0 group had a nearly 10-fold increased risk of progression compared with the amount of increased G3BP1 index.The subgroup analysis showed that the difG3BP1<0 group had a higher risk of progression,regardless of model for end-stage liver disease high-risk or low-risk group.At the same time,compared with the inflam matory marks[tumor necrosis factor-α,interleukin(IL)-1βand IL-18],G3BP1 had higher discrimination and was more stable in the model analysis and validation set.When combined with AFP and LDH,concordance index was respectively 0.84 and 0.8 in training and validation cohorts.CONCLUSION This study indicated that G3BP1 could predict the prognosis of ALF or ACLF patients treated with ALSS.The combination of G3BP1,AFP and LDH could accurately evaluate the disease condition and predict the clinical endpoint of patients.

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.

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.

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.

Viral etiologies of acute liver failure

Acute liver failure(ALF)is a rare cause of liver-related mortality worldwide,with an estimated annual global incidence of more than one million cases.While drug-induced liver injury,including acetaminophen toxicity,is the leading cause of ALF in the Western world,viral infections remain a significant cause of ALF and the most common cause in many developing nations.Given the high mortality rates associated with ALF,healthcare providers should be aware of the broad range of viral infections that have been implicated to enable early diagnosis,rapid treatment initiation when possible,and optimal management,which may include liver transplantation.This review aims to provide a summary of viral causes of ALF,diagnostic approaches,treatment options,and expected outcomes.

Overview of ferroptosis and pyroptosis in acute liver failure

In this editorial,we comment on the article by Zhou et al published in a recent issue.We specifically focus on the crucial roles of ferroptosis and pyroptosis in acute liver failure(ALF),a disease with high mortality rates.Ferroptosis is the result of increased intracellular reactive oxygen species due to iron accumulation,glutathione(GSH)depletion,and decreased GSH peroxidase 4 activity,while pyroptosis is a procedural cell death mediated by gasdermin D which initiates a sustained inflammatory process.In this review,we describe the characteristics of ferroptosis and pyroptosis,and discuss the involvement of the two cell death modes in the onset and development of ALF.Furthermore,we summarize several interfering methods from the perspective of ferroptosis and pyroptosis for the alleviation of ALF.These observations might provide new targets and a theoretical basis for the treatment of ALF,which are also crucial for improving the prognosis of patients with ALF.

Sirtuin 1 in regulating the p53/glutathione peroxidase 4/gasdermin D axis in acute liver failure

In this editorial,we comment on the article by Zhou et al.The study reveals the connection between ferroptosis and pyroptosis and the effect of silent information regulator sirtuin 1(SIRT1)activation in acute liver failure(ALF).ALF is characterized by a sudden and severe liver injury resulting in significant hepatocyte damage,often posing a high risk of mortality.The predominant form of hepatic cell death in ALF involves apoptosis,ferroptosis,autophagy,pyroptosis,and necroptosis.Glutathione peroxidase 4(GPX4)inhibition sensitizes the cell to ferroptosis and triggers cell death,while Gasdermin D(GSDMD)is a mediator of pyroptosis.The study showed that ferroptosis and pyroptosis in ALF are regulated by blocking the p53/GPX4/GSDMD pathway,bridging the gap between the two processes.The inhibition of p53 elevates the levels of GPX4,reducing the levels of inflammatory and liver injury markers,ferroptotic events,and GSDMDN protein levels.Reduced p53 expression and increased GPX4 on deletion of GSDMD indicated ferroptosis and pyroptosis interaction.SIRT1 is a NAD-dependent deacetylase,and its activation attenuates liver injury and inflammation,accompanied by reduced ferroptosis and pyroptosis-related proteins in ALF.SIRT1 activation also inhibits the p53/GPX4/GSDMD axis by inducing p53 acetylation,attenuating LPS/D-GalN-induced 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.

Targeting both ferroptosis and pyroptosis may represent potential therapies for acute liver failure

In this editorial,we comment on the article published in the recent issue of the World Journal of Gastroenterology.Acute liver failure(ALF)is a fatal disease that causes uncontrolled massive hepatocyte death and rapid loss of liver function.Ferroptosis and pyroptosis,cell death forms that can be initiated or blocked concurrently,can play significant roles in developing inflammation and various malignancies.However,their roles in ALF remain unclear.The article discovered the positive feedback between ferroptosis and pyroptosis in the progression of ALF,and revealed that the silent information regulator sirtuin 1(SIRT1)inhibits both pathways through p53,dramatically reducing inflammation and protecting hepatocytes.This suggests the potential use of SIRT1 and its downstream molecules as therapeutics for ALF.Thus,we will discuss the role of ferroptosis and pyroptosis in ALF and the crosstalk between these cell death mechanisms.Additionally,we address potential treatments that could alleviate ALF by simultaneously inhibiting both cell death pathways,as well as examples of SIRT1 activators being used as disease treatment strategies,providing new insights into the therapy of ALF.

sTREM-1 as promising prognostic biomarker for acute-on-chronic liver failure and mortality in patients with acute decompensation of cirrhosis

BACKGROUND Acute decompensation(AD)of cirrhosis is associated with high short-term mortality,mainly due to the development of acute-on-chronic liver failure(ACLF).Thus,there is a need for biomarkers for early and accurate identification of AD patients with high risk of development of ACLF and mortality.Soluble triggering receptor expressed on myeloid cells-1(sTREM-1)is released from activated innate immune cells and correlated with various inflammatory processes.AIM To explore the prognostic value of sTREM-1 in patients with AD of cirrhosis.METHODS A multicenter prospective cohort of 442 patients with cirrhosis hospitalized for AD was divided into a study cohort(n=309)and validation cohort(n=133).Demographic and clinical data were collected,and serum sTREM-1 was measured at admission.All enrolled patients were followed-up for at least 1 year.RESULTS In patients with AD and cirrhosis,serum sTREM-1 was an independent prognosis predictor for 1-year survival and correlated with liver,coagulation,cerebral and kidney failure.A new prognostic model of AD(P-AD)incorporating sTREM-1,blood urea nitrogen(BUN),total bilirubin(TBil),international normalized ratio(INR)and hepatic encephalopathy grades was established and performed better than the model for end-stage liver disease(MELD),MELD-sodium(MELD-Na),chronic liver failure-consortium(CLIF-C)ACLF and CLIF-C AD scores.Additionally,sTREM-1 was increased in ACLF and predicted the development of ACLF during first 28-d follow-up.The ACLF risk score incorporating serum sTREM-1,BUN,INR,TBil and aspartate aminotransferase levels was established and significantly superior to MELD,MELD-Na,CLIF-C ACLF,CLIF-C AD and P-AD in predicting risk of ACLF development.CONCLUSION Serum sTREM-1 is a promising prognostic biomarker for ACLF development and mortality in patients with AD of cirrhosis.

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.

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.

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.

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.

Palliative care for end-stage liver disease and acute on chronic liver failure:A systematic review

BACKGROUND End stage liver disease(ESLD)represents a growing health concern characterized by elevated morbidity and mortality,particularly among individual ineligible for liver transplantation.The demand for palliative care(PC)is pronounced in patients grappling with ESLD and acute on chronic liver failure(ACLF).Unfortunately,the historical underutilization of PC in ESLD patients,despite their substantial needs and those of their family caregivers,underscores the imperative of seamlessly integrating PC principles into routine healthcare practices across the entire disease spectrum.AIM To comprehensively investigate the evidence surrounding the benefits of incorporating PC into the comprehensive care plan for individuals confronting ESLD and/or ACLF.METHODS A systematic search in the Medline(PubMed)database was performed using a predetermined search command,encompassing studies published in English without any restrictions on the publication date.Subsequently,the retrieved studies were manually examined.Simple descriptive analyses were employed to summarize the results.RESULTS The search strategies yielded 721 references.Following the final analysis,32 fulllength references met the inclusion criteria and were consequently incorporated into the study.Meticulous data extraction from these 32 studies was undertaken,leading to the execution of a comprehensive narrative systematic review.The review found that PC provides significant benefits,reducing symptom burden,depressive symptoms,readmission rates,and hospital stays.Yet,barriers like the appeal of transplants and misconceptions about PC hinder optimal utilization.Integrating PC early,upon the diagnosis of ESLD and ACLF,regardless of transplant eligibility and availability,improves the quality of life for these patients.CONCLUSION Despite the substantial suffering and poor prognosis associated with ESLD and ACLF,where liver transplantation stands as the only curative treatment,albeit largely inaccessible,PC services have been overtly provided too late in the course of the illness.A comprehensive understanding of PC's pivotal role in treating ESLD and ACLF is crucial for overcoming these barriers,involving healthcare providers,patients,and caregivers.

Plasma exchange in patients with acute and acute-on-chronic liver failure: A systematic review

BACKGROUND Acute liver failure(ALF)and acute-on-chronic liver(ACLF)carry high short-term mortality rate,and may result from a wide variety of causes.Plasma exchange has been shown in a randomized control trial to improve survival in ALF especially in patients who did not receive a liver transplant.Other cohort studies demonstrated potential improvement in survival in patients with ACLF.AIM To assess utility of plasma exchange in liver failure and its effect on mortality in patients who do not undergo liver transplantation.METHODS Databases MEDLINE via PubMed,and EMBASE were searched and relevant publications up to 30 March,2019 were assessed.Studies were included if they involved human participants diagnosed with liver failure who underwent plasma exchange,with or without another alternative non-bioartificial liver assist device.RESULTS Three hundred twenty four records were reviewed,of which 62 studies were found to be duplicates.Of the 262 records screened,211 studies were excluded.Fifty-one articles were assessed for eligibility,for which 7 were excluded.Twenty-nine studies were included for ALF only,and 9 studies for ACLF only.Six studies included both ALF and ACLF patients.A total of 44 publications were included.Of the included publications,2 were randomized controlled trials,14 cohort studies,12 case series,16 case reports.All of three ALF studies which looked at survival rate or survival days reported improvement in outcome with plasma exchange.In two out of four studies where plasma exchange-based liver support systems were compared to standard medical treatment(SMT)for ACLF,a biochemical improvement was seen.Survival in the non-transplanted patients was improved in all four studies in patients with ACLF comparing plasma exchange vs SMT.Using the aforementioned studies,plasma exchange based therapy in ACLF compared to SMT improved survival in non-transplanted patients at 30 and 90-d with a pooled OR of 0.60(95%CI 0.46-0.77,P<0.01).CONCLUSION The level of evidence for use of high volume plasma exchange in selected ALF cases is high.Plasma exchange in ACLF improves survival at 30-and 90-d in nontransplanted patients.Further well-designed randomized control trials will need to be carried out to ascertain the optimal duration and amount of plasma exchange required and assess if the use of high volume plasma exchange can be extrapolated to patients with ACLF.

Plasma exchange-centered artificial liver support system in hepatitis B virus-related acute-onchronic liver failure:a nationwide prospective multicenter study in China

BACKGROUND： Plasma exchange （PE）-centered artificial liver support system reduced the high mortality rate of hepa titis B virus （HBV）-related acute-on-chronic liver failure （ACLF）. But the data were diverse in different medical centers. The present prospective nationwide study was to evaluate the effects of PE on patients with HBV-ACLF at different stages.

Evaluation of mannitol effect in patients with acute hepatic failure and acute-on-chronic liver failure using conventional MRI,diffusion tensor imaging and in-vivo proton MR spectroscopy

AIM： To evaluate the effect of an intravenous bolus of mannitol in altering brain metabolites, brain water content, brain parenchyma volume, cerebrospinal fluid （CSF） volume and clinical signs in controls and in patients with acute liver failure （ALF） and acute- on-chronic liver failure （ACLF）, by comparing changes in conventional magnetic resonance imaging （MRI）, in vivo proton magnetic resonance spectroscopy （PMRS） and diffusion tensor imaging （DTI） before and after its infusion.METHODS： Five patients each with ALF and ACLF in grade 3 or 4 hepatic encephalopathy and with clinical signs of raised intracranial pressure were studied along with five healthy volunteers. After baseline MRI, an intravenous bolus of 20% mannitol solution was given over 10 min in controls as well as in patients with ALF and ACLE Repeat MRI for the same position was acquired 30 rnin after completing the rnannitol injection. RESULTS： No statistically significant difference was observed between controls and patients with ALF and ACLF in metabolite ratios, DTI metrics and brain volume or CSF volume following 45 rain of mannitol infusion. There was no change in clinical status at the end of post-mannitol imaging. CONCLUSION： The osmotic effect of mannitol did not result in significant reduction of brain water content, alteration in metabolite ratios or any change in the clinical status of these patients during or within 45 min of mannitol infusion.

SOCS3 Expression Correlates with Severity of Inflammation in Mouse Hepatitis Virus Strain 3-induced Acute Liver Failure and HBV-ACLF

Summary： Recently, suppressor of cytokine signaling-3 （SOCS3） has been shown to be an inducible endogenous negative regulator of Janus kinase/signal transducers and activators of transcription （JAK/STAT） pathway which is relevant in inflammatory response, while its functions in acute liver failure and HBV-induced acute-on-chronic liver failure （HBV-ACLF） have not been fully elucidated. In this study, we explored the role of SOCS3 in the development of mouse hepatitis virus strain 3 （MHV-3）-induced acute liver failure and its expression in liver and peripheral blood mononuclear cells （PBMCs） of patients with HBV-ACLF. Inflammation-related gene expression was detected by real-time PCR, immtmohistochemistry and Western blotting. The correlation between SOCS3 level and liver injury was studied. Our results showed that the SOCS3 expression was significantly elevated in both the liver tissue and PBMCs from patients with HBV-ACLF compared to mild chronic hepatitis B （CHB）. Moreover, a time course study showed that SOCS3 level was increased remarkably in the liver of BALB/cJ mice at 72 h post-infection. Pro-inflammatory cytokines, interleukin （IL）-1 β, IL-6, and tumor necrosis factor （TNF）-α, were also increased significantly at 72 h post-infection. There was a close correlation between hepatic SOCS3 level and IL-6, and the severity of liver injury defined by alanine aminotransferase （ALT） and aspartate aminotransferase （AST） levels, respectively. These data suggested that SOCS3 may play a pivotal role in the pathogenesis of MHV-3-induced acute liver failure and HBV-ACLF.

Experimental research on TECA-I bioartificial liver support system to treat canines with acute liver failure

AIM: To evaluate the efficacy and safety of the TECA-I bioartificial liver support system (BALSS) in treating canines with acute liver failure (ALF). METHODS: Ten canines with ALF induced by 80% liver resection received BALSS treatment (BALSS group). Blood was perfused through a hollow fiber tube containing 1X10(10) porcine hepatocytes.Four canines with ALF were treated with BALSS without porcine hepatocytes (control group), and five canines with ALF received drug treatment (drug group). Each treatment lasted 6 hours. RESULTS: BALSS treatment yielded beneficial effects for partial liver resection induced ALF canines with survival and decreased plasma ammonia, ALT, AST and BIL. There was an obvious decrease in PT level and increase in PA level, and there were no changes in the count of lymphocytes, immunoglobulins (IgA, IgG and IgM) and complement (C3 and C4) levels after BALSS treatment. In contrast, for the canines with ALF in non-hepatocyte BALSS group (control group) and drug group, there were no significant changes in ammonia, ALT, AST, BIL, PT and PA levels. ALF canines in BALSS group, control group and drug group lived respectively an average time of 108.0h +/- 12.0h, 24.0h +/- 6.0h and 20.4h +/- 6.4h,and three canines with ALF survived in BALSS group. CONCLUSION: TECA-I BALSS is efficacious and safe for ALF canines induced by partial liver resection.