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.

Heparin is an effective treatment for preventing liver failure after hepatectomy

BACKGROUND Posthepatectomy liver failure(PHLF)is one of the most important causes of death following liver resection.Heparin,an established anticoagulant,can protect liver function through a number of mechanisms,and thus,prevent liver failure.AIM To look at the safety and efficacy of heparin in preventing hepatic dysfunction after hepatectomy.METHODS The data was extracted from Multiparameter Intelligent Monitoring in Intensive Care III(MIMIC-III)v1.4 pinpointed patients who had undergone hepatectomy for liver cancer,subdividing them into two cohorts:Those who were injected with heparin and those who were not.The statistical evaluations used were unpaired ttests,Mann-Whitney U tests,chi-square tests,and Fisher’s exact tests to assess the effect of heparin administration on PHLF,duration of intensive care unit(ICU)stay,need for mechanical ventilation,use of continuous renal replacement therapy(CRRT),incidence of hypoxemia,development of acute kidney injury,and ICU mortality.Logistic regression was utilized to analyze the factors related to PHLF,with propensity score matching(PSM)aiming to balance the preoperative disparities between the two groups.RESULTS In this study,1388 patients who underwent liver cancer hepatectomy were analyzed.PSM yielded 213 matched pairs from the heparin-treated and control groups.Initial univariate analyses indicated that heparin potentially reduces the risk of PHLF in both matched and unmatched samples.Further analysis in the matched cohorts confirmed a significant association,with heparin reducing the risk of PHLF(odds ratio:0.518;95%confidence interval:0.295-0.910;P=0.022).Additionally,heparin treatment correlated with improved short-term postoperative outcomes such as reduced ICU stay durations,diminished requirements for respiratory support and CRRT,and lower incidences of hypoxemia and ICU mortality.CONCLUSION Liver failure is an important hazard following hepatic surgery.During ICU care heparin administration has been proved to decrease the occurrence of hepatectomy induced liver failure.This indicates that heparin may provide a hopeful option for controlling PHLF.

Development and validation of a new prognostic model for patients with acute-on-chronic liver failure in intensive care unit

BACKGROUND Cirrhotic patients with acute-on-chronic liver failure(ACLF)in the intensive care unit(ICU)have a poor but variable prognoses.Accurate prognosis evaluation can guide the rational management of patients with ACLF.However,existing prognostic scores for ACLF in the ICU environment lack sufficient accuracy.AIM To develop a new prognostic model for patients with ACLF in ICU.METHODS Data from 938 ACLF patients in the Medical Information Mart for Intensive Care(MIMIC)database were used to develop a new prognostic model(MIMIC ACLF)for ACLF.Discrimination,calibration and clinical utility of MIMIC ACLF were assessed by area under receiver operating characteristic curve(AUROC),calibration curve and decision curve analysis(DCA),respectively.MIMIC ACLF was then externally validated in a multiple-center cohort,the Electronic Intensive Care Collaborative Research Database and a single-center cohort from the Second Hospital of Hebei Medical University in China.RESULTS The MIMIC ACLF score was determined using nine variables:ln(age)×2.2+ln(white blood cell count)×0.22-ln(mean arterial pressure)×2.7+respiratory failure×0.6+renal failure×0.51+cerebral failure×0.31+ln(total bilirubin)×0.44+ln(internationalized normal ratio)×0.59+ln(serum potassium)×0.59.In MIMIC cohort,the AUROC(0.81/0.79)for MIMIC ACLF for 28/90-day ACLF mortality were significantly greater than those of Chronic Liver Failure Consortium ACLF(0.76/0.74),Model for End-stage Liver Disease(MELD;0.73/0.71)and MELD-Na(0.72/0.70)(all P<0.001).The consistency between actual and predicted 28/90-day survival rates of patients according to MIMIC ACLF score was excellent and superior to that of existing scores.The net benefit of MIMIC ACLF was greater than that achieved using existing scores within the 50%threshold probability.The superior predictive accuracy and clinical utility of MIMIC ACLF were validated in the external cohorts.CONCLUSION We developed and validated a new prognostic model with satisfactory accuracy for cirrhotic patients with ACLF hospitalized in the ICU.The model-based risk stratification and online calculator might facilitate the rational management of patients with ACLF.

Nomogram based on liver stiffness and spleen area with ultrasound for posthepatectomy liver failure:A multicenter study

BACKGROUND Liver stiffness(LS)measurement with two-dimensional shear wave elastography(2D-SWE)correlates with the degree of liver fibrosis and thus indirectly reflects liver function reserve.The size of the spleen increases due to tissue proliferation,fibrosis,and portal vein congestion,which can indirectly reflect the situation of liver fibrosis/cirrhosis.It was reported that the size of the spleen was related to posthepatectomy liver failure(PHLF).So far,there has been no study combining 2D-SWE measurements of LS with spleen size to predict PHLF.This prospective study aimed to investigate the utility of 2D-SWE assessing LS and spleen area(SPA)for the prediction of PHLF in hepatocellular carcinoma(HCC)patients and to develop a risk prediction model.AIM To investigate the utility of 2D-SWE assessing LS and SPA for the prediction of PHLF in HCC patients and to develop a risk prediction model.METHODS This was a multicenter observational study prospectively analyzing patients who underwent hepatectomy from October 2020 to March 2022.Within 1 wk before partial hepatectomy,ultrasound examination was performed to measure LS and SPA,and blood was drawn to evaluate the patient’s liver function and other conditions.Least absolute shrinkage and selection operator logistic regression and multivariate logistic regression analysis was applied to identify independent predictors of PHLF and develop a nomogram.Nomogram performance was validated further.The diagnostic performance of the nomogram was evaluated with receiver operating charac-teristic curve compared with the conventional models,including the model for end-stage liver disease(MELD)score and the albumin-bilirubin(ALBI)score.RESULTS A total of 562 HCC patients undergoing hepatectomy(500 in the training cohort and 62 in the validation cohort)were enrolled in this study.The independent predictors of PHLF were LS,SPA,range of resection,blood loss,international normalized ratio,and total bilirubin.Better diagnostic performance of the nomogram was obtained in the training[area under receiver operating characteristic curve(AUC):0.833;95%confidence interval(95%CI):0.792-0.873;sensitivity:83.1%;specificity:73.5%]and validation(AUC:0.802;95%CI:0.684-0.920;sensitivity:95.5%;specificity:52.5%)cohorts compared with the MELD score and the ALBI score.CONCLUSION This PHLF nomogram,mainly based on LS by 2D-SWE and SPA,was useful in predicting PHLF in HCC patients and presented better than MELD score and ALBI score.

Validation and performance of three scoring systems for predicting primary non-function and early allograft failure after liver transplantation

Background: Primary non-function(PNF) and early allograft failure(EAF) after liver transplantation(LT) seriously affect patient outcomes. In clinical practice, effective prognostic tools for early identifying recipients at high risk of PNF and EAF were urgently needed. Recently, the Model for Early Allograft Function(MEAF), PNF score by King's College(King-PNF) and Balance-and-Risk-Lactate(BAR-Lac) score were developed to assess the risks of PNF and EAF. This study aimed to externally validate and compare the prognostic performance of these three scores for predicting PNF and EAF. Methods: A retrospective study included 720 patients with primary LT between January 2015 and December 2020. MEAF, King-PNF and BAR-Lac scores were compared using receiver operating characteristic(ROC) and the net reclassification improvement(NRI) and integrated discrimination improvement(IDI) analyses. Results: Of all 720 patients, 28(3.9%) developed PNF and 67(9.3%) developed EAF in 3 months. The overall early allograft dysfunction(EAD) rate was 39.0%. The 3-month patient mortality was 8.6% while 1-year graft-failure-free survival was 89.2%. The median MEAF, King-PNF and BAR-Lac scores were 5.0(3.5–6.3),-2.1(-2.6 to-1.2), and 5.0(2.0–11.0), respectively. For predicting PNF, MEAF and King-PNF scores had excellent area under curves(AUCs) of 0.872 and 0.891, superior to BAR-Lac(AUC = 0.830). The NRI and IDI analyses confirmed that King-PNF score had the best performance in predicting PNF while MEAF served as a better predictor of EAD. The EAF risk curve and 1-year graft-failure-free survival curve showed that King-PNF was superior to MEAF and BAR-Lac scores for stratifying the risk of EAF. Conclusions: MEAF, King-PNF and BAR-Lac were validated as practical and effective risk assessment tools of PNF. King-PNF score outperformed MEAF and BAR-Lac in predicting PNF and EAF within 6 months. BAR-Lac score had a huge advantage in the prediction for PNF without post-transplant variables. Proper use of these scores will help early identify PNF, standardize grading of EAF and reasonably select clinical endpoints in relative studies.

Predictive value of NLR, Fib4, and APRI in the occurrence of liver failure after hepatectomy in patients with hepatocellular carcinoma

BACKGROUND Neutrophil-lymphocyte ratio(NLR),fibrosis index based on four factors(Fib4),aspartate aminotransferase-to-platelet ratio index(APRI)can be used for prognostic evaluation of hepatocellular carcinoma.However,no study has established an individualized prediction model for the prognosis of hepatocellular carcinoma based on these factors.AIM To screen the factors that affect the prognosis of hepatocellular carcinoma and establish a nomogram model that predicts postoperative liver failure after hepatic resection in patients with hepatocellular carcinoma.METHODS In total,220 patients with hepatocellular carcinoma treated in our hospital from January 2022 to January 2023 were selected.They were divided into 154 participants in the modeling cohort,and 66 in the validation cohort.Comparative analysis of the changes in NLR,Fib4,and APRI levels in 154 patients with hepatocellular carcinoma before liver resection and at 3 mo,6 mo,and 12 mo postoperatively was conducted.Binary logistic regression to analyze the influencing factors on the occurrence of liver failure in hepatocellular carcinoma patients,roadmap prediction modeling,and validation,patient work characteristic curves(ROCs)to evaluate the predictive efficacy of the model,calibration curves to assess the consistency,and decision curve analysis(DCA)to evaluate the model’s validity were also conducted.RESULTS Binary logistic regression showed that Child-Pugh grading,Surgical site,NLR,Fib4,and APRI were all risk factors for liver failure after hepatic resection in patients with hepatocellular carcinoma.The modeling cohort built a column-line graph model,and the area under the ROC curve was 0.986[95%confidence in terval(CI):0.963-1.000].The patients in the validation cohort utilized the column-line graph to predict the probability of survival in the validation cohort and plotted the ROC curve with an area under the curve of the model of 0.692(95%CI:0.548-0.837).The deviation of the actual outcome curves from the calibration curves of the column-line plots generated by the modeling and validation cohorts was small,and the DCA confirmed the validity.CONCLUSION NLR,Fib4,and APRI independently influence posthepatectomy liver failure in patients with hepatocellular carcinoma.The column-line graph prediction model exhibited strong prognostic capability,with substantial concordance between predicted and actual events.

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.

Current strategies for predicting post-hepatectomy liver failure and a new ultrasound-based nomogram

Liver cancer is associated with a few factors,such as viruses and alcohol con-sumption,and hepatectomy is an important treatment for patients with liver cancer.However,post-hepatectomy liver failure(PHLF)is the most serious complication and has a high mortality rate.Effective prediction of PHLF allows for the adjustment of clinical treatment strategies and is critical to the long-term prognosis of patients.Many factors have been associated with the development of PHLF,so there is an increasing interest in the development of predictive models for PHLF,such as nomograms that integrate intra-operative factors,imaging and biochemical characteristics of the patient.Ultrasound,as a simple and important examination method,plays an important role in predicting PHLF,especially the Nomogram established based on ultrasound measurements of liver stiffness and spleen area provides a more convenient way to predict the occurrence of PHLF.

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.

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.

Mitochondrial dysfunction affects hepatic immune and metabolic remodeling in patients with hepatitis B virus-related acute-onchronic liver failure

BACKGROUND Immune dysregulation and metabolic derangement have been recognized as key factors that contribute to the progression of hepatitis B virus(HBV)-related acute-on-chronic liver failure(ACLF).However,the mechanisms underlying immune and metabolic derangement in patients with advanced HBV-ACLF are unclear.AIM To identify the bioenergetic alterations in the liver of patients with HBV-ACLF causing hepatic immune dysregulation and metabolic disorders.METHODS Liver samples were collected from 16 healthy donors(HDs)and 17 advanced HBV-ACLF patients who were eligible for liver transplantation.The mitochondrial ultrastructure,metabolic characteristics,and immune microenvironment of the liver were assessed.More focus was given to organic acid metabolism as well as the function and subpopulations of macrophages in patients with HBV-ACLF.RESULTS Compared with HDs,there was extensive hepatocyte necrosis,immune cell infiltration,and ductular reaction in patients with ACLF.In patients,the liver suffered severe hypoxia,as evidenced by increased expression of hypoxia-inducible factor-1α.Swollen mitochondria and cristae were observed in the liver of patients.The number,length,width,and area of mitochondria were adaptively increased in hepatocytes.Targeted metabolomics analysis revealed that mitochondrial oxidative phosphorylation decreased,while anaerobic glycolysis was enhanced in patients with HBV-ACLF.These findings suggested that,to a greater extent,hepa-tocytes used the extra-mitochondrial glycolytic pathway as an energy source.Patients with HBV-ACLF had elevated levels of chemokine C-C motif ligand 2 in the liver homogenate,which stimulates peripheral monocyte infiltration into the liver.Characterization and functional analysis of macrophage subsets revealed that patients with ACLF had a high abundance of CD68^(+)HLA-DR^(+)macrophages and elevated levels of both interleukin-1βand transforming growth factor-β1 in their livers.The abundance of CD206^(+)CD163^(+)macrophages and expression of interleukin-10 decreased.The correlation analysis revealed that hepatic organic acid metabolites were closely associated with macrophage-derived cytokines/chemokines.CONCLUSION The results indicated that bioenergetic alteration driven by hypoxia and mitochondrial dysfunction affects hepatic immune and metabolic remodeling,leading to advanced HBV-ACLF.These findings highlight a new therapeutic target for improving the treatment of HBV-ACLF.

Hepatic amyloidosis in a patient with chronic liver failure:A case report

BACKGROUND Amyloidosis is a rare disorder that can be classified into various types,and the most common type is the systemic light chain type.The prognosis of this disease is extremely poor.In general,amyloidosis mainly affects the kidneys and heart and manifests as abnormal proliferation of clonal plasma cells.Cases in which the liver is the primary organ affected by amyloidosis,as in this report,are less common in clinical practice.CASE SUMMARY A 62-year-old man was admitted with persistent liver dysfunction of unknown cause and poor treatment outcomes.His condition persisted,and he developed chronic liver failure,with severe cholestasis in the later stage that was gradually accompanied by renal injury.Ultimately,he was diagnosed with hepatic amyloidosis through liver biopsy and pathological examination.CONCLUSION Hepatic amyloidosis rarely occurs in the clinic,and liver biopsy and pathological examination can assist in the accurate and effective diagnosis of this condition.

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.

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.

Successful treatment of acute liver failure due to Wilson’s disease: Serendipity or fortuity?

BACKGROUND Acute liver failure(ALF)may be the first and most dramatic presentation of Wilson’s disease(WD).ALF due to WD(WD-ALF)is difficult to distinguish from other causes of liver disease and is a clear indication for liver transplantation.There is no firm recommendation on specific and supportive medical treatment for this condition.AIM To critically evaluate the diagnostic and therapeutic management of WD-ALF patients in order to improve their survival with native liver.METHODS A retrospective analysis of patients with WD-ALF was conducted in two pediatric liver units from 2018 to 2023.RESULTS During the study period,16 children(9 males)received a diagnosis of WD and 2 of them presented with ALF.The first was successfully treated with an unconventional combination of low doses of D-penicillamine and zinc plus steroids,and survived without liver transplant.The second,exclusively treated with supportive therapy,needed a hepatotransplant to overcome ALF.CONCLUSION Successful treatment of 1 WD-ALF patient with low-dose D-penicillamine and zinc plus steroids may provide new perspectives for management of this condition,which is currently only treated with liver transplantation.

Kill two birds with one stone:Hapatologist’s approach to metabolic dysfunction-associated steatotic liver disease and heart failure

Heart failure(HF)is a major global public health concern,and one of the less commonly known risk factors for HF development is metabolic dysfunction-associated steatotic liver disease(MASLD),as they share a similar pathophysio-logical background.In this article,we evaluated a recently published review article by Arriola-Montenegro et al.This article briefly summarizes the common pathophysiology of HF and MASLD development and evaluates the available therapeutic options to treat both conditions.Clinical practice guidelines highlight the importance of initiating and titrating guideline-directed medication therapy(GDMT)for patients with HF with reduced ejection fraction.GDMT is comprised of the four pillars currently proposed in most clinical practice guidelines,namely angiotensin-converting enzyme inhibitors(ACEIs),angiotensin receptor blockers(ARBs),angiotensin receptor-neprilysin inhibitors,beta-blockers,mineralocor-ticoid receptor antagonists,and sodium-glucose co-transporter 2 inhibitors(SGLT-2i).Given the similarity of pathophysiology and risk factors,recent studies for GDMT regarding ACEIs,ARBs,mineralocorticoid receptor antagonists,and SGLT-2i have shown beneficial effects on MASLD.Nonetheless,other medications for both conditions and novel therapies require more robust data and well-designed clinical studies to demonstrate their efficacies in both conditions.

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.

Risk factors for secondary infection after liver failure and effect of comprehensive nursing intervention

BACKGROUND In patients with liver failure(LF),the high rate of secondary infections,which are associated with poor prognosis,highlights the clinical significance of understanding the underlying risk factors and implementing targeted intervention programs.AIM To investigate risk factors for secondary infections in patients with LF and evaluate the effectiveness of comprehensive nursing interventions.METHODS This retrospective study included 64 patients with LF,including 32 with and 32 without secondary infections.A questionnaire was used to collect data on age;laboratory parameters,including total and direct bilirubin,prothrombin time,blood ammonia,and other biochemical parameters;invasive procedures;and complications.Patients with secondary infections received comprehensive nursing intervention in addition to routine nursing care,whereas those without secondary infections received only routine nursing care to compare the effect of nursing intervention on outcomes.RESULTS The infection rate,which was not associated with age or complications,was significantly associated with biochemical parameters and invasive procedures(P<0.05).The infection rate was 61.6%in patients who had undergone invasive procedures and 32.1%in those who had not undergone invasive procedures during the hospital stay.The infection rate was also significantly associated with the type of LF(P<0.05),with the lowest rate observed in patients with acute LF and the highest rate observed in those with subacute LF.The nursing satisfaction rate was 58.3%in the uninfected group and 91.7%in the infected group,indicating significantly higher satisfaction in the infected group(P<0.05).CONCLUSION In patients with LF,the rate of secondary infections was high and associated with biochemical parameters and type of LF.Comprehensive nursing intervention can improve patient satisfaction.

Association of preoperative antiviral treatment with incidences of post-hepatectomy liver failure in hepatitis B virus-related hepatocellular carcinoma

BACKGROUND Post-hepatectomy liver failure(PHLF)is a common consequence of radical partial hepatectomy in hepatocellular carcinoma(HCC).AIMS To investigate the relationship between preoperative antiviral therapy and PHLF,as well as assess the potential efficacy of hepatitis B virus(HBV)DNA level in predicting PHLF.METHODS A retrospective study was performed involving 1301 HCC patients with HBV who underwent radical hepatectomy.Receiver operating characteristic(ROC)analysis was used to assess the capacity of HBV DNA to predict PHLF and establish the optimal cutoff value for subsequent analyses.Logistic regression analyses were performed to assess the independent risk factors of PHLF.The increase in the area under the ROC curve,categorical net reclassification improvement(NRI),and integrated discrimination improvement(IDI)were used to quantify the efficacy of HBV DNA level for predicting PHLF.The P<0.05 was considered statistically significant.RESULTS Logistic regression analyses showed that preoperative antiviral therapy was independently associated with a reduced risk of PHLF(P<0.05).HBV DNA level with an optimal cutoff value of 269 IU/mL(P<0.001)was an independent risk factor of PHLF.All the reference models by adding the variable of HBV DNA level had an improvement in area under the curve,categorical NRI,and IDI,particularly for the fibrosis-4 model,with values of 0.729(95%CI:0.705-0.754),1.382(95%CI:1.341-1.423),and 0.112(95%CI:0.110-0.114),respectively.All the above findings were statistically significant.CONCLUSION In summary,preoperative antiviral treatment can reduce the incidence of PHLF,whereas an increased preoperative HBV DNA level has a correlative relationship with an increased susceptibility to PHLF.