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Aim: Myostatin is a myokine involved in muscle mass regulation. The associations between circulating myostatin levels and clinical characteristics in patients with acute liver failure (ALF) and late‐onset hepatic failure (LOHF) are unclear. Methods: In this retrospective study, 51 patients with ALF or LOHF were included. Serum myostatin was measured using an enzyme‐linked immunosorbent assay. Results: Myostatin levels were significantly lower in patients with ALF and LOHF than in controls (ALF/LOHF: 2522 pg/mL, controls: 3853 pg/mL, p = 0.003). The prevalence of low myostatin in deceased patients was significantly higher than that in spontaneous survivors and patients who underwent liver transplantation. Patients with low myostatin levels had a high incidence of complications. There was a positive correlation between the psoas muscle index and serum myostatin levels. Patients with low myostatin levels had shorter 1‐year transplant‐free survival and shorter 1‐year overall survival than patients with high myostatin levels. Low serum myostatin levels were associated with poor prognosis independent of the Japanese scoring system for ALF ≥3, King's College criteria, or model for end‐stage liver disease score >30.5. The combination of serum myostatin levels and prognostic models for ALF significantly stratified patients according to 1‐year prognosis. Conclusions: Low serum myostatin levels were associated with a low psoas muscle index, complication rate, and poor prognosis in patients with ALF and LOHF. Assessment of circulating myostatin levels may improve the prediction of outcomes in patients with ALF and LOHF. [ABSTRACT FROM AUTHOR]

Background: Although acute hepatitis caused by varicella zoster virus mostly develops in immunocompromised patients, hyperacute liver failure is very rare. To our knowledge, there are no previous reports on liver transplant patients. Methods: We report the first case of fatal hyperacute liver failure due to varicella zoster virus immediately after living‐donor liver transplantation without cutaneous lesions and review the literature. Result: The present case exhibited rapid development and progression of acute liver failure from postoperative days 11–13, despite being seropositive for varicella zoster virus but unvaccinated and on immunosuppression before transplantation. Especially in solid organ transplantation, only six cases of severe acute liver failure that included hepatic encephalopathy and/or impaired consciousness and sudden extremely high (> 4000 U/L) serum aspartate aminotransferase levels have been reported in heart, lung, and kidney transplant patients. Conclusions: Early diagnosis of hyperacute liver failure due to varicella zoster virus is challenging because the disease progresses rapidly and skin lesions are absent. [ABSTRACT FROM AUTHOR]

Clinical manifestations of congenital syphilis (CS) include liver disease with/without impaired liver function, identified as syphilitic hepatitis. Hepatic involvement may be dramatic; therefore, early diagnosis is crucial to provide treatment and prevent fatal outcomes. A new resurgence of CS cases has been described in recent years worldwide. We reported our experience with a case series of infants hospitalized for liver disease with a final diagnosis of CS, highlighting the wide spectrum of liver involvement, the rapid progression in cases with late diagnosis, and the pitfalls of the management of this forgotten but reemerging disease. A retrospective analysis of CS patients with hepatic presentation in the period 2008–2023 was conducted. We collected five cases (three female) with a median age of 13.8 days (range 1–84 days). In three cases, mothers were not screened for syphilis during pregnancy, and in two cases, they were seronegative in the first trimester screening. None practiced specific therapy during pregnancy. Hepatic involvement was characterized by hepatosplenomegaly, in four cases associated with cholestatic jaundice and in three cases with liver failure. Rapid plasma reagin (RPR) and Treponema pallidum hemagglutination assay (TPHA) were positive in all cases in mothers and infants. CS presented with multiorgan involvement and was fatal in one case. Conclusions: It is important to consider CS in infants with cholestasis and acute liver failure, but also in sick infants with isolated hepatomegaly. Early recognition of infants with CS is critical to identify missed cases during pregnancy and to start early treatment. What is known: • In recent years, it has been seen an increase of congenital syphilis cases in both low- and middle-income countries. • In most cases, infants born to mothers untreated for syphilis appear normal without signs of infection at birth but may develop manifestations of the disease after months or years if left untreated. • What is new: • Congenital syphilis is an emerging problem that may result in multiorgan involvement with liver disease predominant at onset. • It is important to consider congenital syphilis in infants with cholestasis and liver failure, but also in sick infants with isolated hepatomegaly. [ABSTRACT FROM AUTHOR]

Acute liver failure (ALF), associated with a clinical fatality rate exceeding 80%, is characterized by severe liver damage resulting from various factors in the absence of pre-existing liver disease. The role of microbiota in the progression of diverse liver diseases, including ALF, has been increasingly recognized, with the interactions between the microbiota and the host significantly influencing both disease onset and progression. Despite growing interest in the microbiological aspects of ALF, comprehensive reviews remain limited. This review critically examines the mechanisms and efficacy of microbiota-based treatments for ALF, focusing on their role in prevention, treatment, and prognosis over the past decade. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) are highly effective in the treatment of acute liver failure (ALF). The efficacy of MSCs is closely related to the inflammatory environment. Therefore, we investigated the functional changes of MSCs in response to interleukin‐33 (IL‐33) stimulation. The results showed that bone marrow mesenchymal stem cells (BMSCs) pretreated with IL‐33 had increased CCR2 expression, targeted CCL2 in the injured liver tissue, and improved the migration ability. Under LPS stimulation, the NF‐κB pathway of BMDM was activated, and its phenotype polarized to the M1‐type, while BMSCs pretreated with IL‐33 inhibited the NF‐κB pathway and enhanced M2 macrophage polarization. The M2‐type macrophages could further inhibit hepatocytes inflammation, reduce hepatocytes apoptosis, and promote hepatocytes repair. These results suggest that IL‐33 can enhance the efficacy of BMSCs in ALF and provide a new strategy for cell therapy of liver diseases. [ABSTRACT FROM AUTHOR]

Liver biopsies have consistently contributed to our understanding of the pathogenesis and aetiologies of acute liver disease. As other diagnostic modalities have been developed and refined, the role of biopsy in the management of patients with acute liver failure (ALF), acute‐on‐chronic liver failure (ACLF) and acute hepatitis, including acute liver injury (ALI), has changed. Liver biopsy remains particularly valuable when first‐line diagnostic algorithms fail to determine aetiology. Despite not being identified as a mandatory diagnostic tool in recent clinical guidelines for the management of ALF or ACLF, many centres continue to undertake biopsies given the relative safety of transjugular biopsy in this setting. Several studies have demonstrated that liver biopsy can provide prognostic information, particularly in the context of so‐called indeterminate hepatitis, and is extremely useful in excluding conditions such as metastatic tumours that would preclude transplantation. In addition, its widespread use of percutaneous biopsies in cases of less severe acute liver injury, for example in the establishment of a diagnosis of acute presentation of autoimmune hepatitis or confirmation of a probable or definite drug‐induced liver injury (DILI), has meant that many centres have seen a shift in the ratio of specimens they are receiving from patients with chronic to acute liver disease. Histopathologists therefore need to be equipped to deal with these challenging specimens. This overview provides an insight into the contemporary role of biopsies (as well as explant and autopsy material) in diagnosing acute liver disease. It outlines up‐to‐date clinical definitions of liver injury and considers recent recommendations for the diagnosis of AIH and drug‐induced, autoimmune‐like hepatitis (DI‐AIH). [ABSTRACT FROM AUTHOR]

Acute liver failure (ALF) is an acute liver disease with a high mortality rate in clinical practice, characterized histologically by extensive hepatocellular necrosis and massive neutrophil infiltration. However, the role of these abnormally infiltrating neutrophils during ALF development is unclear. Here, in an ALF mouse model, metabolites were identified that promote the formation of neutrophil extracellular traps (NETs) in the liver, subsequently influencing macrophage differentiation and disease progression. ALF occurs with abnormalities in hepatic and intestinal metabolites. Abnormal metabolites (LTD4 and glutathione) can directly, or indirectly via reactive oxygen species, promote NET formation of infiltrating neutrophils, which subsequently regulate macrophages in a pro‐inflammatory M1‐like state, inducing an amplification of the destructive effects of inflammation. Together, this study provides new insights into the role of NETs in the pathogenesis of ALF. [ABSTRACT FROM AUTHOR]

Paediatric acute liver failure (PALF) is often characterised by its rapidity of onset and potential for significant morbidity and even mortality. Patients often develop multiorgan dysfunction/failure, including severe acute kidney injury (AKI). Whilst the management of PALF focuses on complications of hepatic dysfunction, the associated kidney impairment can significantly affect patient outcomes. Severe AKI requiring continuous kidney replacement therapy (CKRT) is a common complication of both PALF and liver transplantation. In both scenarios, the need for CKRT is a poor prognostic indicator. In adults, AKI has been shown to complicate ALF in 25–50% of cases. In PALF, the incidence of AKI is often higher compared to other critically ill paediatric ICU populations, with reports of up to 40% in some observational studies. Furthermore, those presenting with AKI regularly have a more severe grade of PALF at presentation. Observational studies in the paediatric population corroborate this, though data are not as robust—mainly reflecting single-centre cohorts. Perioperative benefits of CKRT include helping to clear water-soluble toxins such as ammonia, balancing electrolytes, preventing fluid overload, and managing raised intracranial pressure. As liver transplantation often takes 6–10 h, it is proposed that these benefits could be extended to the intraoperative period, avoiding any hiatus. Intraoperative CKRT (IoCKRT) has been shown to be practicable, safe and may help sicker recipients tolerate the operation with outcomes analogous with less ill patients not requiring IoCKRT. Here, we provide a comprehensive guide describing the rationale, practicalities, and current evidence base surrounding IoCKRT during transplantation in the paediatric population. [ABSTRACT FROM AUTHOR]

We report a case of a 17 year old lady who presented with severe abdominal pain for 4 days. Patient developed fulminant hepatitis and disseminated intravascular coagulation during her hospital stay. History of Ratol (3% yellow phosphorus) ingestion was revealed on the second day of admission. She was managed with NAC infusion for 3 days along with supportive treatment and was discharged on the 10th day of admission. Accidental ingestion of Ratol is common in rural India. Early diagnosis and management of yellow phosphorus can improve the outcome of the patient. It is important to identify predictors of outcome of patients with toxin-induced liver injury. [ABSTRACT FROM AUTHOR]

Bioartificial livers have showcased significant value in the treatment of acute liver failure (ALF). Current efforts are directed toward overcoming challenges in the development of microcarriers, with a specific emphasis on integrating higher‐density liver cells to enhance detoxification capabilities. Here, inspired by the radial filtration model in hepatic lobules, ion‐specific silk fibroin microcarriers are proposed with biomimetic niches for cultivating functional liver cells at high density. These biomimetic microcarriers are generated by capillary microfluidic device with controllable adjustments of ion type or concentration within the aqueous phase. When cultivating human induced pluripotent stem cell ‐differentiated mature liver cells on these recrystallized microcarriers, notably enhanced cell proliferation activity, as well as increased metabolic and secretory functionality is observed. Based on these features, the microcarrier‐integrated bioreactor can effectively reduce hepatic transaminase levels and significantly improve urea, albumin production, and survival rate in rabbit ALF models is demonstrated. Thus, it is believed that the biomimetic microcarriers and their derived bioreactor may hold potential for clinical applications in managing ALF and other liver diseases. [ABSTRACT FROM AUTHOR]

Acute liver failure (ALF) involves extensive necrosis of liver cells and severe impairment of liver function. Hepatocyte transplantation holds promise for treating ALF by swiftly supporting liver functions and promoting liver regeneration. However, the scarcity of suitable cell sources requires strategies to obtain enough functional hepatocyte‐like cells (HLCs) and optimize their in vivo transplantation efficiency. A DNA hexahedral nanostructure (DHN) is developed loaded with microRNA‐122 to efficiently induce hepatic differentiation of human adipose‐derived mesenchymal stem cells into HLCs. These HLCs can serve as alternative hepatocyte sources, as confirmed by expression of liver‐specific genes and proteins, and the restoration of liver functions. To enhance in vivo survival efficiency of HLCs, a versatile scaffold is also created by 3D printing the calcium‐cross‐linked mixture bioink composed of sodium alginate, gelatin, and silk fibroin with excellent ROS scavenging capabilities. The scaffold is infused with chitosan‐DHN hydrogel containing HLCs for tissue engineering orthotopic transplantation in CCl4‐induced ALF mice. The transplanted composite scaffold‐HLCs successfully repair tissue necrosis in the liver injury area of mice and regulate expressions of genes and proteins associated with inflammation, oxidative stress, and hepatocyte function. Collectively, this study offers a novel approach and strategy for identifying alternative hepatocyte sources and treating ALF. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate the clinical and molecular genetic characteristics of ten children with ornithine carbamoyltransferase deficiency (OTCD) in southeastern China, as well as the correlation between the genotype and phenotype of OTCD. Methods: A retrospective analysis was performed on the clinical manifestations, laboratory testing, and genetic test findings of ten children with OTCD admitted between August 2015 and October 2021 at Quanzhou Maternity and Children's Hospital of Fujian Province in China. Results: Five boys presented with early-onset symptoms, including poor appetite, drowsiness, groaning, seizures, and liver failure. In contrast, five patients (one boy and four girls) had late-onset gastrointestinal symptoms as the primary clinical manifestation, all presenting with hepatic impairment, and four with hepatic failure.Nine distinct variants of the OTC gene were identified, including two novel mutations: c.1033del(p.Y345Tfs*50) and c.167T > A(p.M56K). Of seven patients who died, five had early-onset disease despite active treatment. Three patients survived, and two of them underwent liver transplantation. Conclusions: The clinical manifestations of OTCD lack specificity. However, elevated blood ammonia levels serve as a crucial diagnostic clue for OTCD. Genetic testing aids in more accurate diagnosis and prognosis assessment by clinicians. In addition, we identified two novel pathogenic variants and expand the mutational spectrum of the gene OTC, which may contribute to a better understanding of the clinical and genetic characteristics of OTCD patients. [ABSTRACT FROM AUTHOR]

Background and Aim Methods Results Conclusion Acute liver failure (ALF) is a fatal clinical syndrome of severe hepatic dysfunction. Chemokines promote liver diseases by recruiting and activating immune cells. We aimed to investigate the role of C–C chemokine ligand 25 (CCL25) in ALF.An ALF mouse model induced by D‐galactosamine/lipopolysaccharide was evaluated through liver hematoxylin and eosin staining and serum transaminase and cytokine measurement. CCL25 expression in serum was analyzed by ELISA and in liver by immunohistochemical staining and western blot. C–C chemokine receptor 9 (CCR9)‐expressing cells in the liver were identified by immunofluorescence staining. The effects of anti‐CCL25 on ALF were evaluated in vivo. Cytokine expression and migration of CCL25‐stimulated RAW264.7 macrophages were studied. We also investigated the role of anti‐CCL25 and BMS‐345541, an NF‐κB signaling inhibitor, in vitro. NF‐κB activation was assessed via western blot, and p65 nuclear translocation was detected using cellular immunofluorescence.ALF mice showed severe histological damage and high serum levels of aminotransferase and inflammatory cytokines. Elevated CCL25 and NF‐κB activation was observed in vivo. CCR9 was expressed on macrophages in ALF mouse liver. ALF was suppressed after anti‐CCL25 treatment, with significant NF‐κB inhibition. In vitro, CCL25 induced strong migration and cytokine release in RAW264.7 macrophages, which were eliminated by anti‐CCL25 and BMS‐345541. Furthermore, the NF‐κB activation and p65 nuclear translocation induced by CCL25 were also inhibited by anti‐CCL25 and BMS‐345541.CCL25 contributes to ALF development by inducing macrophage‐mediated inflammation via activation of the NF‐κB signaling. [ABSTRACT FROM AUTHOR]

Introduction: Liver dysfunction is common in patients with hemophagocytic lymphohistiocytosis (HLH). However, whether the severity of liver injury is associated with the prognosis of patients with HLH remains to be determined. This study aims to assess the association of the severity of liver involvement with short-term prognosis among adult patients with HLH. Methods: A retrospective study was performed from January 2012 to December 2020, including 150 patients with newly diagnosed HLH and liver injury. Results: The majority of our cohort suffered from mild to moderate hepatic damage, presenting with Child-Turcotte-Pugh (CTP) class A (55, 36.7%) or B (74, 49.3%). The prevalence of acute liver failure (ALF) was 9.3% in our cohort. The overall 30-day mortality rate was 49.3% among the study population. HLH patients with ALF showed an extremely adverse prognosis, with a mortality rate as high as 92.9%. In a multivariate analysis, age ≥60 years (p = 0.016), blood urea nitrogen (BUN) ≥7 μmol/L (p < 0.001), and malignancy-associated HLH (p < 0.001) at the diagnosis of HLH were identified as being strongly correlated with 30-day prognosis. An excellent predictive power was found. Among the predictive scores used to assess early death of HLH patients with liver injury, the prognostic efficiency of chronic liver failure-sequential organ failure assessment (CLIF-SOFA) (AUROC: 0.936 ± 0.0211) and SOFA score (0.901 ± 0.026) were significantly better than those of the APACHE II (p < 0.001), model for end-stage liver disease score (p < 0.001) and CTP scores (p < 0.001). Conclusion: Patients with old age, elevated BUN, and malignancy had inferior survival. CLIF-SOFA and SOFA enable more accurate prediction of early death in HLH patients with liver injury than other liver-specific and general prognostic models. [ABSTRACT FROM AUTHOR]

Background: Fulminant hepatitis is a rare and severe form of acute liver failure (ALF) characterized by rapid and massive destruction of liver cells and associated with a high mortality rate. Infectious factors, in particular viral hepatitis, take a prominent place in the etiology of ALF, however, the presence of chronic liver pathology can play a significant role in the disease progression and development of ALF. Case Presentation: A 2-year-old child was hospitalized on the 4th day of the disease with manifestations of jaundice and general intoxication. The examination revealed markers of active hepatitis A virus infection and Epstein-Barr virus infection. From the seventh day of the disease, the child's condition began to progressively deteriorate due to manifestations of ALF. Despite the use of immunomodulatory and replacement therapy, the disease ended fatally on the 9th day. Pathohistological examination revealed manifestations of viral necrotic hepatitis on the background of autoimmune sclerosing cholangitis. Conclusion: The case is novel as regards the occurrence of two viral hepatitis with different modes of transmission on a background of unidentified liver disease. [ABSTRACT FROM AUTHOR]

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Background: Histopathological characterization obtained by transjugular liver biopsy (TJLB) may theoretically contribute to clarification of the exact aetiology of acute liver failure (ALF). It's unclear whether the histopathological information from TJLB, due to the small specimen size, significantly contributes to diagnosing ALF causes, guiding therapy decisions, or predicting overall prognosis. This retrospective study aimed to analyse safety and clinical significance of TJLB in patients with ALF. Methods: This retrospective, monocentric study investigated safety and efficacy of TJLB in patients with ALF over a ten-year period at a tertiary care transplant-center. The predictive value of various clinical and laboratory characteristics as well as histopathological findings obtained by TJLB on 28-day liver-transplant-free survival were evaluated by calculating uni- and multivariate Cox-proportional hazard regression models. Additional univariate logistic regression analyses were performed to explore the influence of degree of intrahepatic necrosis on the secondary endpoints intensive-care-unit (ICU) admission, need for endotracheal intubation, renal replacement therapy and high-urgency listing for LTX. Results: A total of 43 patients with ALF receiving TJLB were included into the study. In most cases (n = 39/43 cases) TJLB confirmed the initially already clinically presumed ALF aetiology and the therapeutic approach was unchanged by additional histological examination in the majority of patients (36/43 cases). However, in patients with a high suspicion for aetiologies potentially treatable by medical immunosuppression (e.g. AIH, GvHD), TJLB significantly influenced further treatment planning and/or adjustment. While the degree of intrahepatic necrosis showed significance in the univariate analysis (p = 0.04), it did not demonstrate a significant predictive effect on liver transplant-free survival in the multivariate analysis (p = 0.1). Only consecutive ICU admission was more likely with higher extent of intrahepatic necrosis (Odds ratio (OR) 1.04 (95% CI 1–1.08), p = 0.046). Conclusions: Performance of TJLB in ALF led to a change in suspected diagnosis and to a significant change in therapeutic measures only in those patients with a presumed high risk for aetiologies potentially responsive to immunosuppressive therapy. Clinical assessment alone was accurate enough, with additional histopathological examination adding no significant value, to predict overall prognosis of patients with ALF. [ABSTRACT FROM AUTHOR]

Background: N-acetyl cysteine (NAC) has been shown to be effective in the treatment of non-acetaminopheninduced acute liver failure. NAC has anti-inflammatory, inotropic, and vasodilatory properties. It has also shown to improve microcirculation and oxygen delivery in cases of liver failure. Rodenticide poisoning affects many vital organs in the body including liver thereby causing acute liver failure with a high mortality rate. Our study aimed to examine the clinical parameters of rodenticide poisoning patients and compare the severity of liver failure and the outcome after NAC treatment. Methods: From 2019 to 2021, a prospective study was conducted at Trichy SRM Hospital and Research Centre, Tamilnadu on patients who had a history of ingesting rat killer paste(RKP), a potent rodenticide. Patients who presented with RKP poisoning were administered NAC irrespective of the duration of poison intake, as an initial loading dose of 150 mg/kg infused in 200ml of 5% dextrose over 1 hour, followed by 50 mg/kg in 500ml of 5% dextrose over the next 4 hours, and then 100 mg/kg in 1000ml of 5% dextrose over the next 16 hours. The presence of liver injury or bleeding diathesis was assessed clinically and biochemically. Statistical analysis was done using chi-square test to compare the groups. Results: Among the 57 patients who were treated with NAC, 16 expired and 41 recovered. Development of Jaundice(p=0.02), hepatitis(p=0.028) and hypotension had highly significant (p < 0.01) correlation with the delay in time of presentation to the ICU which marks the time of NAC administration. Mortality was observed in these set of patients who had increased serum transaminases, bilirubin and prolonged PT & aPTT. Conclusion: In this study, patients who received NAC earlier had a higher percentage of complete recovery. Earlier administration use of NAC has prevented the emergence of negative outcomes. [ABSTRACT FROM AUTHOR]

Acute liver failure (ALF) induces increased energy expenditure and disrupts the metabolism of essential nutrients. Hepatic encephalopathy is a complication of ALF with a poor prognosis and mainly involves the metabolic disturbance of amino acids in its pathogenesis. In this review, we discuss the nutritional management for ALF in consideration of the pathophysiology of ALF with respect to the impairment of hepatocyte function. It is known that enteral nutrition is recommended for patients with ALF, while parenteral nutrition is recommended for patients who cannot tolerate enteral nutrition. As ALF leads to a hypermetabolic state, the energy intake is recommended to cover 1.3 times the resting energy expenditure. Because of the high risk of hypoglycemia associated with disturbances in glucose metabolism, substantial glucose intake is recommended. Along with the deterioration of glucose metabolism, protein metabolism is also disrupted. As patients with ALF have increased systemic protein catabolism together with decreased protein synthesis, appropriate amounts of amino acids or protein under monitoring serum ammonia levels are recommended. In conclusion, nutritional management based on the understanding of nutritional pathophysiology is a pivotal therapeutic approach for patients with ALF. The approach should be individualized in the acute phase, the recovery phase, and the pretransplant phase. [ABSTRACT FROM AUTHOR]

Patients with acute liver failure (ALF) and acute on chronic liver failure (ACLF) have significant morbidity and mortality. They require extracorporeal blood purification modalities like continuous renal replacement therapy (CRRT) and therapeutic plasma exchange (TPE) as a bridge to recovery or liver transplantation. Limited data are available on the outcomes of patients treated with these therapies. This is a retrospective single-center study of 23 patients from 2015 to 2022 with ALF/ACLF who underwent CRRT and TPE. We aimed to describe the clinical characteristics and outcomes of these patients. Median (IQR) age was 0.93 years (0.57, 9.88), range 16 days to 20 years. Ten (43%) had ALF and 13 (57%) ACLF. Most (n = 19, 82%) started CRRT for hyperammonemia and/or hepatic encephalopathy and all received TPE for refractory coagulopathy. CRRT was started at a median of 2 days from ICU admission, and TPE started on the same day in most. The liver transplant was done in 17 (74%), and 2 recovered native liver function. Four patients, all with ACLF, died prior to ICU discharge without a liver transplant. The median peak ammonia pre-CRRT was 131 µmol/L for the whole cohort. The mean (SD) drop in ammonia after 48 h of CRRT was 95.45 (43.72) µmol/L in those who survived and 69.50 (21.70) µmol/L in those who did not (p 0.26). Those who survived had 0 median co-morbidities compared to 2.5 in non-survivors (aOR (95% CI) for mortality risk of 2.5 (1.1–5.7), p 0.028). Conclusion: In this cohort of 23 pediatric patients with ALF or ACLF who received CRRT and TPE, 83% survived with a liver transplant or recovered with their native liver. Survival was worse in those who had ACLF and those with co-morbid conditions. What is Known: • Pediatric acute liver failure is associated with high mortality. • Patients may require extracorporeal liver assist therapies (like CRRT, TPE, MARS, SPAD) to bridge them over to a transplant or recovery of native liver function. What is New: • Standard volume plasma exhange has not been evaluated against high volume plasma exchange for ALF. • The role, dose, and duration of therapeutic plasma exchange in patients with acute on chronic liver failure is not well described. [ABSTRACT FROM AUTHOR]

Introduction: Acute hepatic failure due to yellow phosphorus rodenticide ingestion is often lethal. This study aimed to analyze demographic characteristics and prognostic indicators, focusing on hyperlactataemia as a potential early indicator of mortality in patients poisoned with yellow phosphorus rodenticide. Materials and methods: This was a retrospective study of 96 patients poisoned with a yellow phosphorus-containing rodenticide (Ratol paste, which contains 3% yellow phosphorus). We examined demographic details, clinical symptoms, and biochemical markers to identify prognostic indicators. Results: Demographics were similar among survivors and non-survivors. Mortality (36.5%) correlated with a higher ingested dose and treatment delays, with a mean (±SD) of 5.26 ± 2.2 survival days among those who died. Symptoms, including gastrointestinal and neurological features, typically appeared 48 h after ingestion. Non-survivors developed increased aminotransferase activities (74.3%), prolonged prothrombin time (65.7%), and hyperbilirubinaemia (65.7%) during hospitalization, significantly more commonly compared to survivors (P < 0.0001). Hyperlactataemia (lactate concentration >2 mmol/L) was present in 97.1% of non-survivors, with increased serial lactate concentrations observed in 88.6%. The median (interquartile range) admission lactate concentration among non-survivors was 4.6 mmol/L (3.36–7.53 mmol/L), and their peak median (interquartile range) lactate concentration was 6.1 mmol/L (8.74–10.6 mmol/L). In non-survivors, an increased lactate concentration preceded increased aminotransferase activities and prolonged prothrombin time. Logistic regression and receiver operating characteristic curve analysis confirmed that a 24 h lactate concentration ≥2.67 mmol/L predicted death with 94.3% sensitivity and 91.8% specificity. Discussion: The majority of patients who ingest yellow phosphorus remain asymptomatic initially and typically present to hospital following the onset of gastrointestinal symptoms, usually a day later. As progression to death occurs within a week of yellow phosphorus ingestion in most cases, determining prognosis as early as possible enables swift referral to a liver transplant centre. Based on our study, a 24 h lactate concentration ≥2.67 mmol/L appears to be an early prognostic indicator of death. In another study, a lactate concentration >5.8 mmol/L was found to be a poor prognostic indicator. Conclusions: Hyperlactataemia on admission and increased serial lactate concentrations appear to be early poor prognostic signs in patients with yellow phosphorus-induced liver failure. [ABSTRACT FROM AUTHOR]

Background and Aims: Autoimmune hepatitis (AIH) in children presenting in acute liver failure (ALF) can be fatal and often requires liver transplantation (LTx). This individual patient data meta‐analysis (IPD) aims to examine management and outcomes of this population, given the lack of large cohort studies on paediatric AIH first presenting as ALF (AIH‐ALF). Methods: A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta‐Analyses of IPD statement using PubMed and Excerpta Medica dataBASE, and included English studies published between 2000 and 2020. The study included patients under 21 years of age, diagnosed with type 1 or 2 AIH and presenting with ALF. Data extracted included clinical and biochemical characteristics, interventions, and outcomes. Results: Three hundred and thirty eligible patients from 61 studies were identified, with an additional five patients from our institution. The majority were female (66.8%), with a median age of 10. Overall, 59.7% achieved native liver survival (NLS), 35% underwent LTx, and 5% died before LTx. The use of corticosteroids with non‐steroid immunomodulators increased the likelihood of NLS by 2.5‐fold compared to corticosteroids alone. AIH‐1 was associated with 3.3‐fold odds for NLS, compared to AIH‐2. However, on multivariate analysis, only AIH‐1 was identified as an independent predictor for NLS (OR 3.8 [95% CI 1.03–14.2], p =.04). Conclusion: While corticosteroids and non‐steroid immunomodulators treatment may offer enhanced probability of achieving NLS, treatment regimens for AIH‐ALF may need to consider patient‐specific factors, especially AIH type. This highlights the potential for NLS in AIH‐ALF and suggest a need to identify biomarkers which predict the need for combination immunosuppression to avoid LTx. [ABSTRACT FROM AUTHOR]

Background and Aims: Acute liver failure is a multisystem disorder with a high mortality and frequent need for emergency liver transplantation. Following massive innate immune system activation, soluble markers of macrophage activation are released during liver damage and their association with disease severity and prognosis requires exploration. Methods: Patients ALF from the United States Acute Liver Failure Study Group (USALFSG, n = 224) and King's College Hospital (n = 40) together with healthy controls (HC, n = 50) were recruited. Serum from early (Days 1–3) and late (>Day 3) time points were analysed for MAMs by enzyme‐linked immunosorbent assay correlated to markers of illness severity and 21‐day spontaneous survival. Surface expression phenotyping was performed via Flow Cytometry on CD14+ monocytes. Results: All MAMs serum concentrations were significantly higher in ALF compared to controls (p <.0001). sCD206 concentration was higher in early and late stages of the disease in patients with bacteraemia (p =.002) and infection in general (p =.006). In MELD‐adjusted multivariate modelling, sCD206 and sCD163 were independently associated with mortality. CD14+ monocyte expression of CD206 (p <.001) was higher in patients with ALF compared with controls and correlated with SOFA score (p =.018). sCD206 was independently validated as a predictor of infection in an external cohort. Conclusions: sCD206 is increased in serum of ALF patients with infections and poor outcome and is upregulated on CD14+ monocytes. Later measurements of sCD163 and sCD206 during the evolution of ALF have potential as mechanistic predictors of mortality. sCD206 should be explored as a biomarker of sepsis and mortality in ALF. [ABSTRACT FROM AUTHOR]

Acute liver failure is a life‐threatening syndrome, for which liver transplantation is presently the most effective treatment. Unfortunately, such treatment is extremely limited by a shortage of donor organs. Stem cell therapy offers a promising treatment strategy for acute liver failure. Yet, therapeutic efficacy and potential are hampered by administration route and safety concerns. In this work, we fabricated menstrual blood‐derived stem cells‐conditioned medium/polymersome hybrid nanoparticles that were self‐assembled from amphiphilic block copolymers via the direct hydration method and encapsulated therapeutic bioactive factors within the aqueous core of vesicles. The merit of vesicular architecture enabled the loading capacity of distinct proteins and the maintenance of biological activity. These hybrid nanoparticles can be steadily taken up into cytoplasm and promote hepatocyte proliferation in vitro. Prolonged in vivo circulation time brought higher accumulation in livers. The therapeutic nanoparticles alleviated hepatic injury and promoted liver recovery in mice with carbon tetrachloride‐induced liver failure. Considering the feasibility and benefit of the hybrid nanoparticle therapy, it provided a potential strategy to treat acute liver failure. [ABSTRACT FROM AUTHOR]

Acute liver failure is a syndrome that occurs in 20-59% of patients with liver pathology and is one of the main causes of death in 40% of patients with mechanical jaundice of benign origin and in more than 70% of cases of tumor obstruction of the biliary tract and cancer of caput pancreas. In most cases, the syndrome is a consequence of acute liver damage (viral or drug-induced). Still, it can occur with longterm obstructive jaundice, be the first manifestation of Wilson's disease, autoimmune chronic hepatitis, or superinfection of the hepatitis D virus against the background of chronic hepatitis B. The aim of the work was to study the pathophysiological features of the development of acute liver failure in patients with bile outflow disorders. The pathogenesis of acute liver failure caused by cholestasis is based on the damage and death of hepatocytes due to impaired blood circulation in the liver, as well as the toxic effect on the parenchyma of both the etiological factors themselves and their metabolites. The first week from the onset of symptoms is very important and usually accompanied by a systemic inflammatory response syndrome with significant consequences. At the same time, the main factors influencing the results of treatment of patients at different points in time are the combination of the critical functional reserve of the liver and the nature and severity of liver damage. In the case of the development of a systemic inflammatory response syndrome, there is a further increase in inflammation, which has a systemic nature and leads to the failure of other organs. Under these circumstances, understanding the pathophysiological features of the course of acute liver failure makes it possible to carry out the necessary diagnostic measures on time and offer appropriate therapy. [ABSTRACT FROM AUTHOR]

Acute liver failure is a life-threatening organ dysfunction with systemic organ involvement and is associated with significant mortality and morbidity unless specific management is undertaken. This meta-analysis aimed to assess the effects of intravenous N-acetylcysteine (NAC) on mortality and the length of hospital stay in patients with non-acetaminophen acute liver failure. Two hundred sixty-six studies from four databases were screened, and four randomized control trials were included in the final analysis. Our results could not demonstrate increased overall survival (OR 0.70, 95% CI [0.34, 1.44], p = 0.33) or transplant-free survival (OR 0.90, 95% CI [0.25, 3.28], p = 0.87) in patients treated with intravenous NAC. We observed an increased overall survival in adult patients treated with NAC (OR 0.59, 95% CI [0.35, 0.99], p = 0.05) compared to pediatric patients, but whether this is attributed to the age group or higher intravenous dose administered remains unclear. We did not observe a decreased length of stay in NAC-treated patients (OR −5.70, 95% CI [−12.44, 1.05], p = 0.10). In conclusion, our meta-analysis could not demonstrate any significant benefits on overall and transplant-free patient survival in non-acetaminophen ALF. Future research should also focus on specific etiologies of ALF that may benefit most from the use of NAC. [ABSTRACT FROM AUTHOR]

Interactions of hepatic macrophages with local inflammatory microenvironment is the key factor promoting the development of acute liver failure (ALF). Hence, reprogramming pro-inflammatory M1 into anti-inflammatory M2 phenotype may offer a promising strategy for treating ALF by targeting inflammation. Our group found Carvedilol possessed potential anti-inflammatory property previously, which had been scarcely reported in ALF. We present a synergy strategy to induce macrophages into the phenotype M2-type anti-inflammatory macrophages with interleukin-4 (IL-4) and IL-10 at first. Then Carvedilol is loaded on the macrophage membrane-camouflaged biomimetic nano-platform (termed as M2M@CNP) to evade reticuloendothelial system (RES) and afford Carvedilol delivery to the inflammatory environment with overproduced reactive oxygen species (ROS), further prolonging its circulation and accumulation. Sustainably released Carvedilol produced anti-inflammatory, antioxidant and anti-apoptosis effects, combining local M2-type cell membranes (M2-CM) inhibited pro-inflammatory cytokines and ROS levels, which in turn promoted and amplified M1 to M2 phenotype polarization efficiency. This study offers new insights into the rational design of biomimetic nanosystems for safe and effective ALF therapy to accelerate the clinical translation. [ABSTRACT FROM AUTHOR]

Background: Infantile liver failure syndrome type 1 (ILFS1, OMIM #615,438), caused by leucyl-tRNA synthase 1 (LARS1, OMIM *151,350) deficiency, is a rare autosomal-recessive disorder. The clinical manifestations, molecular-genetic features, and prognosis of LARS1 disease remain largely elusive. Methods: Three new instances of ILFS1 with confirmed variants in LARS1, encoding LARS1, were identified. Disease characteristics were summarized together with those of 33 reported cases. Kaplan-Meier analysis was performed to assess prognostic factors in ILFS1 patients. Results: The 3 new ILFS1 patients harbored 6 novel variants in LARS1. Among the 36 known patients, 12 died or underwent liver transplantation. The main clinical features of ILFS1 were intrauterine growth restriction (31/32 patients in whom this finding was specifically described), failure to thrive (30/31), hypoalbuminemia (32/32), microcytic anemia (32/33), acute liver failure (24/34), neurodevelopmental delay (25/30), seizures (22/29), and muscular hypotonia (13/27). No significant correlations were observed between genotype and either presence of liver failure or clinical severity of disease. Kaplan-Meier analysis indicated that age of onset < 3mo (p = 0.0015, hazard ratio = 12.29, 95% confidence interval [CI] = 3.74–40.3), like liver failure (p = 0.0343, hazard ratio = 6.57, 95% CI = 1.96-22.0), conferred poor prognosis. Conclusions: Early age of presentation, like liver failure, confers poor prognosis in ILFS1. Genotype-phenotype correlations remain to be established. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) is a nonhepatotropic virus. It causes mild self-limiting illness characterized by fever, oral ulcer, diarrhea, lymphadenopathy, and hepatosplenomegaly. Rarely it causes acute liver failure (ALF). EBV-related ALF (EBV-ALF) accounts for 0.2% of all ALF cases. The prognosis of EBV-ALF is dismal, and it can affect both immunocompromised and immunocompetent individuals. We performed a partial autopsy on a 30-year-old immunocompetent individual with infectious mononucleosis and ALF. The autopsy showed characteristic histomorphology of EBV-ALF in the form of centrizonal confluent hepatocytic necrosis, portal mixed inflammatory infiltrate, sinusoidal lymphocytosis, numerous hemophagocytic figures, and tissue Epstein-Barr encoded RNA-in situ hybridization (EBER-ISH) positivity. Extensive hemophagocytosis was noted in the liver, spleen, lymph node, and bone marrow. Other features include T-zone expansion of lymph nodes and spleen, interstitial pneumonia pattern in the lungs, and exanthematous skin changes. EBV-DNA polymerase chain reaction from the postmortem blood sample yielded 70,200 copies/µL. The index case highlights the uncommon occurrence of EBV-ALF, its histomorphological features, and its putative pathogenesis. [ABSTRACT FROM AUTHOR]

Acute liver failure is an infrequent yet fatal condition marked by rapid liver function decline, leading to abnormalities in blood clotting and cognitive impairment among individuals without prior liver ailments. The primary reasons for liver failure are infection with hepatitis virus or overdose of certain medicines, such as acetaminophen. Phaeodactylum tricornutum (PT), a type of microalgae known as a diatom species, has been reported to contain an active ingredient with anti-inflammatory and anti-obesity effects. In this study, we evaluated the preventive and therapeutic activities of PT extract in acute liver failure. To achieve our purpose, we used two different acute liver failure models: acetaminophen- and D-GalN/LPS-induced acute liver failure. PT extract showed protective activity against acetaminophen-induced acute liver failure through attenuation of the inflammatory response. However, we failed to demonstrate the protective effects of PT against acute liver injury in the D-GalN/LPS model. Although the PT extract did not show protective activity against two different acute liver failure animal models, this study clearly demonstrates the importance of considering the differences among animal models when selecting an acute liver failure model for evaluation. [ABSTRACT FROM AUTHOR]

Background: Acute liver failure (ALF) following yellow phosphorous (YP) ingestion is similar to acetaminophen‐induced ALF and it has become a public concern in our region. This study assessed low volume therapeutic plasma exchange (LV‐TPE) efficacy in improving the transplant free survival in YP poisoning. Methods: Adult patients with toxicology reports of YP and ALF requiring critical care were included in the study. LV‐TPE was planned for three consecutive days and three more if required. Performed 1.3 to 1.5 plasma volume replacing with 0.9% normal saline, 5% human albumin solution, and fresh frozen plasma based on ASFA 2019 criteria. MELD score, laboratory parameters, LV‐TPE details were captured. The study end point was clinical outcome of the patients. Results: Among 36 patients, 19 underwent LV‐TPE and 17 opted out of LV‐TPE and they were included as a control arm. The MELD score was 32.64 ± 8.05 and 37.83 ± 9.37 in both groups. There were 13 survivors in LV‐TPE group leading to a 68.42% reduction in mortality. The coagulation and biochemical parameters showed a significant percentage change after LV‐TPE. Refractory shock, delay in initiating procedure and acidosis were independent predictors of mortality. Conclusion: A well‐timed LV‐TPE improves the survival of patients with ALF due to YP poisoning. [ABSTRACT FROM AUTHOR]

In this study, a mixed porcine–human bioengineered liver (MPH-BEL) was used in a preclinical setup of extracorporeal liver support devices as a treatment for a model of post-resection liver failure (PRLF). The potential for human clinical application is further illustrated by comparing the functional capacity of MPH-BEL grafts as assessed using this porcine PRLF model with fully human (FH-BEL) grafts which were perfused and assessed in vitro. BEL grafts were produced by reseeding liver scaffolds with HUVEC and primary porcine hepatocytes (MPH-BEL) or primary human hepatocytes (FH-BEL). PRLF was induced by performing an 85% liver resection in domestic white pigs and randomized into the following three groups 24 h after resection: standard medical therapy (SMT) alone, SMT + extracorporeal circuit (ECC), and SMT + MPH-BEL. The detoxification and metabolic functions of the MPH-BEL grafts were compared to FH-BEL grafts which were perfused in vitro. During the 24 h treatment interval, INR values normalized within 18 h in the MPH-BEL therapy group and urea synthesis increased as compared to the SMT and SMT + ECC control groups. The MPH-BEL treatment was associated with more rapid decline in hematocrit and platelet count compared to both control groups. Histological analysis demonstrated platelet sequestration in the MPH-BEL grafts, possibly related to immune activation. Significantly higher rates of ammonia clearance and metabolic function were observed in the FH-BEL grafts perfused in vitro than in the MPH-BEL grafts. The MPH-BEL treatment was associated with improved markers of liver function in PRLF. Further improvement in liver function in the BEL grafts was observed by seeding the biomatrix with human hepatocytes. Methods to reduce platelet sequestration within BEL grafts is an area of ongoing research. [ABSTRACT FROM AUTHOR]

Inflammation plays a critical role in conditions such as acute liver failure, acute-on-chronic liver failure, and ischemia–reperfusion-induced liver injury. Various pathogenic pathways contribute to liver inflammation, involving inflammatory polarization of macrophages and Küpffer cells, neutrophil infiltration, dysregulation of T cell subsets, oxidative stress, and activation of hepatic stellate cells. While mesenchymal stromal cells (MSCs) have demonstrated beneficial properties, their clinical translation is limited by their cellular nature. However, MSC-derived extracellular vesicles (MSC-EVs) have emerged as a promising cell-free therapeutic approach for immunomodulation. MSC-EVs naturally mirror their parental cell properties, overcoming the limitations associated with the use of MSCs. In vitro and in vivo preclinical studies have demonstrated that MSC-EVs replicate the beneficial effects of MSCs in liver injury. This includes the reduction of cell death and oxidative stress, improvement of hepatocyte function, induction of immunomodulatory effects, and mitigation of cytokine storm. Nevertheless, MSC-EVs face challenges regarding the necessity of defining consistent isolation methods, optimizing MSCs culture conditions, and establishing quality control measures for EV characterization and functional assessment. By establishing standardized protocols, guidelines, and affordable cost mass production, clinicians and researchers will have a solid foundation to conduct further studies, validate the therapeutic efficacy of MSC-EVs, and ultimately pave the way for their clinical implementation in acute liver injury. [ABSTRACT FROM AUTHOR]

Acute liver failure (ALF) is a life-threatening disease with high mortality. Given excessive inflammation is one of the major pathogenesis of ALF, candidates targeting inflammation could be beneficial in the condition. Now the effect of hyperactivated succinate dehydrogenase (SDH) on promoting inflammation in lipopolysaccharide (LPS)-treated macrophages has been studied. However, its role and mechanism in ALF is not well understood. Here intraperitoneal injection of D -galactosamine and LPS was conducted in male C57BL/6 J mice to induce the ALF model. Dimethyl malonate (DMM), which inhibited SDH activity, was injected intraperitoneally 30 min before ALF induction. Macrophage pyroptosis was induced by LPS plus adenosine triphosphate (ATP). Pyroptosis-related molecules and proteins including GSDMD oligomer were examined by ELISA and western blot techniques, respectively. ROS production was assessed by fluorescence staining. The study demonstrated SDH activity was increased in liver macrophages from ALF mice. Importantly, DMM administration inhibited ROS, IL-1β, and pyroptosis-associated proteins levels (NLRP3, cleaved caspase-1, GSDMD-N, and GSDMD oligomers) both in the ALF model and in macrophages stimulated with LPS plus ATP. In vitro, ROS promoted pyroptosis by facilitating GSDMD oligomerization. Additionally, when ROS levels were increased through the addition of H 2 O 2 to the DMM group, the levels of GSDMD oligomers were reverted. In conclusion, SDH hyperactivation promotes macrophage pyroptosis by ROS-mediated GSDMD oligomerization, suggesting that targeting this pathway holds promise as a strategy for treating ALF and other inflammatory diseases. [Display omitted] • Hyperactivation of SDH in liver macrophages is associated with ALF mice. • Increased SDH activity promotes pyroptosis in macrophages by ROS in vitro and in vivo. • ROS accelerates macrophage pyroptosis by GSDMD oligomerization. [ABSTRACT FROM AUTHOR]

BACKGROUND: Acute Liver Failure (ALF) is a critical medical condition with rapid development, often caused by viral infections, hepatotoxic drug abuse, or other severe liver diseases. Timely and accurate prediction of ALF occurrence is clinically crucial. However, predicting ALF poses challenges due to the diverse physiological differences among patients and the dynamic nature of the disease. OBJECTIVE: This study introduces a deep learning approach that combines fully connected and convolutional neural networks for effective ALF prediction. The goal is to overcome limitations of traditional machine learning methods and enhance predictive model performance and generalization. METHODS: The proposed model integrates a fully connected neural network for handling basic patient features and a convolutional neural network dedicated to capturing temporal patterns in patient data. The combination allows automatic learning of complex patterns and abstract features present in highly dynamic medical data associated with ALF. RESULTS: The model's effectiveness is demonstrated through comprehensive experiments and performance evaluations. It outperforms traditional machine learning methods, achieving 94.8% accuracy and superior generalization capabilities. CONCLUSIONS: The study highlights the potential of deep learning in ALF prediction, emphasizing the importance of considering individualized medical factors. Future research should focus on improving model robustness, addressing imbalanced data, and further exploring personalized features for enhanced predictive accuracy in real-world clinical scenarios. [ABSTRACT FROM AUTHOR]

Acute liver failure, commonly caused by acetaminophen overdose, is associated with numerous systemic complications including cerebral edema, hypotension, acute kidney injury, and infection. Management is primarily supportive, with an emphasis on excellent neurocritical care. Although some antidotes and targeted treatments exist, the only definitive treatment remains orthotopic liver transplant. [ABSTRACT FROM AUTHOR]

Acute liver failure (ALF) is a serious inflammatory disorder with high mortality rates, which poses a significant threat to human health. The IL-33/ST2 signal is a crucial regulator in inflammation responses associated with lipopolysaccharide (LPS)-induced macrophages. The IL-17A signaling pathway promotes the release of chemokines and inflammatory cytokines, recruiting neutrophils and T cells under LPS stimulation, thus facilitating inflammatory responses. Here, the potential therapeutic benefits of neutralizing the IL-17A signal and modulating the IL-33/ST2 signal in ALF were investigated. A novel dual-functional fusion protein, anti-IL-17A-sST2, was constructed, which displayed high purity and biological activities. The administration of anti-IL-17A-sST2 resulted in significant anti-inflammatory benefits in ALF mice, amelioration of hepatocyte necrosis and interstitial congestion, and reduction in TNF-α and IL-6. Furthermore, anti-IL-17A-sST2 injection downregulated the expression of TLR4 and NLRP3 as well as important molecules such as MyD88, caspase-1, and IL-1β. The results suggest that anti-IL-17A-sST2 reduced the secretion of inflammatory factors, attenuated the inflammatory response, and protected hepatic function by regulating the TLR4/MyD88 pathway and inhibiting the NLRP3 inflammasome, providing a new therapeutic approach for ALF. [ABSTRACT FROM AUTHOR]

Gasdermin D (GSDMD) is a widely expressed protein that can be activated by inflammatory factors within hepatocytes. Once activated, the N terminal domain of GSDMD (GSDMD N) will form pores, leading to rupture of cell membranes and leakage of cytoplasm, ultimately leading to cell death. Pyrozosis is the most characteristic mode of inflammatory lytic cell death mediated by GSDMD. Recent studies have found that activation of GSDMD amplifies the inflammatory response and induces pyrosis of liver cells, thereby accelerating the progression of acute liver failure. This article focuses on the pathogenic mechanism and potential therapeutic targets of GSDMD mediated hepatocyte pyrozosis in acute liver failure, in order to provide new ideas for finding potential intervention targets for the effective treatment of acute liver failure. [ABSTRACT FROM AUTHOR]

Background: Extensive hepatocyte mortality and the absence of specific medical therapy significantly contribute to the unfavorable prognosis of acute liver failure (ALF). Ferroptosis is a crucial form of cell death involved in ALF. In this study, we aimed to determine the impact of Mediator complex subunit 1 (Med1) on ferroptosis and its potential hepatoprotective effects in ALF. Results: Med1 expression is diminished in the liver of lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced ALF mice, as well as in hepatocytes damaged by H2O2 or TNF-α/D-GalN in vitro. Med1 overexpression mitigates liver injury and decreases the mortality rate of ALF mice by ferroptosis inhibition. The mechanism by which Med1 inhibits erastin-induced ferroptosis in hepatocytes involves the upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream antioxidant genes heme oxygenase-1 (HO-1), glutamate cysteine ligase catalytic (GCLC), and NAD(P)H quinone oxidoreductase 1 (NQO1). Furthermore, Med1 overexpression suppresses the transcription of proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the liver of mice with LPS/D-GalN-induced ALF. Conclusion: Overall, our research findings indicate that Med1 suppresses ferroptosis and alleviates liver injury in LPS/D-GalN-induced ALF through the activation of Nrf2. These findings substantiate the therapeutic viability of targeting the Med1-Nrf2 axis as a means of treating individuals afflicted with ALF. [ABSTRACT FROM AUTHOR]

Acute liver failure (ALF) results from severe liver damage or end-stage liver disease. It is extremely fatal and causes serious health and economic burdens worldwide. Once ALF occurs, liver transplantation (LT) is the only definitive and recommended treatment; however, LT is limited by the scarcity of liver grafts. Consequently, the clinical use of bioartificial liver (BAL) has been proposed as a treatment strategy for ALF. Human primary hepatocytes are an ideal cell source for these methods. However, their high demand and superior viability prevent their widespread use. Hence, finding alternatives that meet the seed cell quality and quantity requirements is imperative. Stem cells with self-renewing, immunogenic, and differentiative capacities are potential cell sources. MSCs and its secretomes encompass a spectrum of beneficial properties, such as anti-inflammatory, immunomodulatory, anti-ROS (reactive oxygen species), anti-apoptotic, pro-metabolomic, anti-fibrogenesis, and pro-regenerative attributes. This review focused on the recent status and future directions of stem cell-based strategies in BAL for ALF. Additionally, we discussed the opportunities and challenges associated with promoting such strategies for clinical applications. [ABSTRACT FROM AUTHOR]

The route of administration of implanted cells may affect the outcome of cell therapy by directing cell migration to the damaged site. However, the question of the relationship between the route of administration, the efficacy of colonisation of a given organ, and the efficacy of cell therapy has not been resolved. The aim of the study was to localise transplanted intravenously and intraperitoneally human amniotic epithelial cells (hAECs) in the tissues of mice, both healthy and injured, in an animal experimental model of acute liver failure (ALF). Mice intoxicated with D-Galactosamine (D-GalN) at a dose of 150 mg/100 g body weight received D-GalN alone or with a single dose of hAECs administered by different routes. Subsequently, at 6, 24, and 72 h after D-GaIN administration and at 3, 21, and 69 h after hAEC administration, lungs, spleen, liver, and blood were collected from recipient mice. The degree of liver damage and regeneration was assessed based on biochemical blood parameters, histopathological evaluation (H&E staining), and immunodetection of proliferating (Ki67+) and apoptotic (Casp+) cells. The biodistribution of the administered cells was based on immunohistochemistry and the identification of human DNA. It has been shown that after intravenous administration, in both healthy and intoxicated mice, most of the transplanted hAECs were found in the lungs, while after intraperitoneal administration, they were found in the liver. We concluded that a large number of hAECs implanted in the lungs following intravenous administration can exert a therapeutic effect on the damaged liver, while the regenerative effect of intraperitoneally injected hAECs on the liver was very limited due to the relatively lower efficiency of cell engraftment. [ABSTRACT FROM AUTHOR]

Objectives: Acute liver failure (ALF) is associated with high morbidity and mortality. Timely liver transplantation (LT) is the only universally accepted therapy for ALF that is non-responsive to medical therapy. Data regarding the use of living donor LT (LDLT) for this indication in the US is scarce. Materials and Methods: United Network of Organ Sharing/Organ Procurement and Transplantation Network (UNOS/OPTN) data from January 2002 to December 2020 were reviewed. Adult and pediatric recipients listed as status 1 were included. Demographics, clinical and laboratory data, and post-LT survival rates were compared for LDLT vs. DDLT recipients. Results: There were 180 LDLT (3.6%) and 4779 DDLT (96.4%) recipients with a diagnosis of ALF. The majority of recipients in the LDLT group were pediatric (n = 164, 91%) compared to the DDLT group (n = 1455, 30%), p < 0.001. In the pediatric-only group, post-LT survival was comparable between LDLT and DDLT recipients (p = 0.15). Five-year post-LT survival was higher for pediatric recipients compared to adults in the LDLT group (84.2% vs. 62.5%, respectively, p < 0.001) and the DDLT group (82.8% vs. 78.7%, respectively, p < 0.001). Adults had a higher hazard of death compared to pediatric recipients in the LDLT group (HR = 3.560, 95% CI 1.612–7.844, p = 0.002) and the DDLT group (HR = 1.472, 95% CI 1.290–1.679, p < 0.001). In multivariate analysis results, the type of LT and age group were not associated with higher post-LT mortality. Conclusions: In the US, LDLT constitutes 3.6% of LTs for ALF. In the pediatric-only group, post-LT survival was comparable between LDLT and DDLT recipients. Overall, there were superior post-LT outcomes for pediatric recipients compared to adults for LDLT and DDLT. [ABSTRACT FROM AUTHOR]

Background: Liver transplantation remains the only curative treatment for end-stage liver diseases. Unfortunately, there is a drastic organ donor shortage. Hepatocyte transplantation emerged as a viable alternative to liver transplantation. Considering their unique expansion capabilities and their potency to be driven toward a chosen cell fate, pluripotent stem cells are extensively studied as an unlimited cell source of hepatocytes for cell therapy. It has been previously shown that freshly prepared hepatocyte-like cells can cure mice from acute and chronic liver failure and restore liver function. Methods: Human PSC-derived immature hepatic progenitors (GStemHep) were generated using a new protocol with current good manufacturing practice compliant conditions from PSC amplification and hepatic differentiation to cell cryopreservation. The therapeutic potential of these cryopreserved cells was assessed in two clinically relevant models of acute liver failure, and the mode of action was studied by several analytical methods, including unbiased proteomic analyses. Results: GStemHep cells present an immature hepatic phenotype (alpha-fetoprotein positive, albumin negative), secrete hepatocyte growth factor and do not express major histocompatibility complex. A single dose of thawed GStemHep rescue mice from sudden death caused by acetaminophen and thioacetamide-induced acute liver failure, both in immunodeficient and immunocompetent animals in the absence of immunosuppression. Therapeutic biological effects were observed as soon as 3 h post-cell transplantation with a reduction in serum transaminases and in liver necrosis. The swiftness of the therapeutic effect suggests a paracrine mechanism of action of GStemHep leading to a rapid reduction of inflammation as well as a rapid cytoprotective effect with as a result a proteome reprograming of the host hepatocytes. The mode of action of GStemHep relie on the alleviation of inhibitory factors of liver regeneration, an increase in proliferation-promoting factors and a decrease in liver inflammation. Conclusions: We generated cryopreserved and current good manufacturing practice-compliant human pluripotent stem cell-derived immature hepatic progenitors that were highly effective in treating acute liver failure through rapid paracrine effects reprogramming endogenous hepatocytes. This is also the first report highlighting that human allogeneic cells could be used as cryopreserved cells and in the absence of immunosuppression for human PSC-based regenerative medicine for acute liver failure. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate the efficacy of exosomes derived from mesenchymal stem cells on animal models of acute liver failure. METHODS: PubMed, Web of Science, Embase, The Cochrane Library, CBM, CNKI, WanFang, and VIP databases were retrieved from inception to January 16, 2023. A series of animal experiments on the treatment of acute liver failure animal models by exosomes derived from mesenchymal stem cells were collected. Two evaluators screened the literature and extracted the data independently. The bias risk was evaluated by the SYRCLE tool. The extracted data were analyzed by Revmen 5.4.1 software and Stata 17.0 software. RESULTS: A total of 241 articles were retrieved and 9 animal experiments were included, with 219 animals: 110 animals in the model group and 109 animals in the exosome group. The results showed that the survival rate of animals in the exosome group improved significantly [RR=9.34, 95%CI(3.91, 22.29), P < 0.001], the levels of serum alanine transaminase [SMD=-5.31, 95%CI(-7.43, -3.19), P < 0.001] and aspartate aminotransferase [SMD=-4.47, 95%CI(-5.85, -3.10), P < 0.001] were reduced obviously. The expressions of interleukin-1β [SMD=-11.54, 95%CI(-18.12, -4.95), P=0.000 6], interleukin-6 [SMD=-5.75, 95%CI(-8.08, -3.41), P < 0.001] and tumor necrosis factor-α [SMD=-4.46, 95%CI(-6.83, -2.09), P=0.000 2], were suppressed obviously. CONCLUSION: Exosomes derived from mesenchymal stem cells effectively inhibit the inflammatory response, ameliorate liver function of animals with acute liver failure, and improve their survival rate. The results of subgroup analysis showed that the shorter survival time of animals (≤ 24 hours), the lower dose of transplanted exosomes (< 1 mg/kg) and the source of exosomes (adipose-derived mesenchymal stem cells) may affect the efficacy of the exosomes derived from mesenchymal stem cells in the animal model of acute liver failure. This conclusion and its clinical transformation still need to be confirmed by randomized controlled studies with large sample sizes and high quality. [ABSTRACT FROM AUTHOR]

Inflammatory cytokine storms can trigger disease exacerbation and even death and have reached a consensus in the clinical treatment of acute organ failure. However, the existing strategies remain a great challenge to efficiently suppress inflammatory cytokine storms for promoting organ repair and regeneration. Herein, fully human umbilical cord (UC)-derived adhesive materials (UCAM) that integrate decellularized extracellular matrix (ECM) nanofiber hydrogel and homologous mesenchymal stem cells (MSCs) are demonstrated to greatly suppress inflammatory cytokine storms, demonstrating high efficacy in treating acute liver failure (ALF) in rats with 90% hepatectomy. The UC-derived adhesive materials have the capacity to secrete a significant quantity of cytokines by MSCs to recruit activated immune cells to migrate into their ECM nanofiber networks, segregating them away from the infection area and thereby greatly suppressing the inflammatory cytokine storms. As expected, the UC-derived adhesive materials can significantly promote hepatocyte proliferation to achieve functional recovery and regeneration of the liver, significantly improving the survival rate in rats. Our fully human UC-derived adhesive materials provide a new avenue in suppressing inflammatory cytokine storms for promoting organ regeneration that would be really utility in clinical organ transplantation-related treatment. [ABSTRACT FROM AUTHOR]

Background and Aims: To systematically review the literature for reports on Wolcott‐Rallison syndrome, focusing on the spectrum and natural history, genotype‐phenotype correlations, patient and native liver survival, and long‐term outcomes. Methods: PubMed, Livio, Google Scholar, Scopus and Web of Science databases were searched. Data on genotype, phenotype, therapy, cause of death and follow‐up were extracted. Survival and correlation analyses were performed. Results: Sixty‐two studies with 159 patients met the inclusion criteria and additional 30 WRS individuals were collected by personal contact. The median age of presentation was 2.5 months (IQR 2) and of death was 36 months (IQR 50.75). The most frequent clinical feature was neonatal diabetes in all patients, followed by liver impairment in 73%, impaired growth in 72%, skeletal abnormalities in 59.8%, the nervous system in 37.6%, the kidney in 35.4%, insufficient haematopoiesis in 34.4%, hypothyroidism in 14.8% and exocrine pancreas insufficiency in 10.6%. Episodes of acute liver failure were frequently reported. Liver transplantation was performed in six, combined liver‐pancreas in one and combined liver‐pancreas‐kidney transplantation in two individuals. Patient survival was significantly better in the transplant cohort (p =.0057). One‐, five‐ and ten‐year patient survival rates were 89.4%, 65.5% and 53.1%, respectively. Liver failure was reported as the leading cause of death in 17.9% of cases. Overall survival was better in individuals with missense mutations (p =.013). Conclusion: Wolcott‐Rallison syndrome has variable clinical courses. Overall survival is better in individuals with missense mutations. Liver‐ or multi‐organ transplantation is a feasible treatment option to improve survival. [ABSTRACT FROM AUTHOR]

Introduction and Objectives: Acute liver failure, also known as fulminant hepatic failure (FHF), includes a spectrum of clinical entities characterized by acute liver injury, severe hepatocellular dysfunction and hepatic encephalopathy. The objective of this study was to assess cerebral autoregulation (CA) in 25 patients (19 female) with FHF and to follow up with seventeen of these patients before and after liver transplantation. Patients and Methods: The mean age was 33.8 years (range 14-56, SD 13.1 years). Cerebral hemodynamics was assessed by transcranial Doppler (TCD) bilateral recordings of cerebral blood velocity (CBv) in the middle cerebral arteries (MCA). Results: CA was assessed based on the static CA index (SCAI), reflecting the effects of a 20-30 mmHg increase in mean arterial blood pressure on CBv induced with norepinephrine infusion. SCAI was estimated at four time points: pretransplant and on the 1st, 2nd and 3rd posttransplant days, showing a significant difference between pre- and posttransplant SCAI (p = 0.005). SCAI peaked on the third posttransplant day (p = 0.006). Categorical analysis of SCAI showed that for most patients, CA was reestablished on the second day posttransplant (SCAI > 0.6). Conclusions: These results suggest that CA impairment pretransplant and on the 1st day posttransplant was re-established at 48-72 h after transplantation. These findings can help to improve the management of this patient group during these specific phases, thereby avoiding neurological complications, such as brain swelling and intracranial hypertension. [ABSTRACT FROM AUTHOR]

Background: Pediatric acute liver failure (PALF) with undetermined etiology is associated with higher liver transplantation and lower spontaneous recovery (transplant‐free) rates. The diagnostic odyssey in PALF cases hinders appropriate management and follow‐up after liver transplantation. Advances in whole exome sequencing analysis have already been successful at identifying new genetic causes of PALF. Case Presentation: We report a 17‐year‐old girl who underwent liver transplantation at the age of 7 months due to acute liver failure and presented later with abnormal neurological manifestations, that is, gait disturbances, dysarthria, and mental retardation that led us to the diagnosis of SCYL1 deficiency. Conclusion: PALF cases should be screened for possible underlying genetic disorders. Genetic studies and reanalysis of whole‐genome sequencing data may help identify new cases and clarify the genotype–phenotype correlation. SCYL1 deficiency should be suspected in PALF patients who develop neurological involvement after LT. Early diagnosis is vital for proper management of ALF crises in SCYL1 deficiency patients. Despite the reported favorable outcomes of ALF crises in SCYL1 deficiency, liver transplantation decision should be discussed on a case‐by‐case basis. [ABSTRACT FROM AUTHOR]

Background: Pediatric acute liver failure (PALF) is one of the most demanding emergencies in hepatology, intensive care, and for transplant team. This report describes the clinical pattern, diagnostic and therapeutic modalities in children with ALF considered at risk of death without liver transplantation, basing on a long‐term experience of the pediatric transplant center. Materials and Methods: Between 1990 and 2022, 104 children aged 7 days–17 years (median 8 years), with body weight 3.1 to 77 kg (median 32 kg), were qualified for LT due to ALF, and finally 81 (78%) of them were transplanted (9% of all 899 LT performed in children in the same period). Results: A total of 23 children were not transplanted: 15 (14.4%) died while awaiting transplantation. In 8 (7.7%) patients liver function recovered. Before transplantation 45 (43.3%) children developed circulatory failure, in 66 (63.5%) mechanical ventilation was necessary, 18 patients presented acute kidney injury (17.3%), and encephalopathy higher than stage I was present in 60 (57.7%) patients. In 63 children, various kidney/liver assist procedures were performed: CVVHD (continuous veno‐venous hemodiafiltration in 22 (21.2%) patients, albumin dialysis (MARS; molecular adsorbent recirculating system) in 39 (37.5%) patients, therapeutic plasma exchange (TPE) in 13 (12.5%) patients. Twenty (24.7%) children died after LT including 15 (18.5%) in the early posttransplant period, and 5 (6.1%) in the late follow‐up. Conclusions: Treatment of children with ALF in the peritransplant period is very difficult and require an experienced, multidisciplinary team. Despite continued advances in the care of children with ALF, patient survival remains lower than for elective indications for liver transplantation, and timely qualification and transplantation still are the most important factors of survival of these children. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the clinical efficacy and safety of fractionated plasma separation and adsorption integrated with continuous veno‐venous hemofiltration (FPSA‐CVVH) treatment in patients with acute liver failure (ALF). Methods: In this retrospective study, we enrolled patients with ALF (serum total bilirubin >10 mg/dL or Model for End‐Stage Liver Disease [MELD] Score >18) hospitalized between August 2017 and August 2022. All patients had at least two sessions of FPSA‐CVVH. The primary measure of treatment efficacy was the reduction ratios (RRs) of bilirubin after each session of FPSA‐CVVH. Results: Seventy‐eight patients with ALF were enrolled. The MELD score at baseline was 22.9 ± 7.5. The mean total bilirubin was 22.05 ± 5.94 mg/dL, direct bilirubin was 16.33 ± 4.60 mg/dL and indirect bilirubin was 3.43 ± 1.60 mg/dL. One hundred and eighty seven sessions of FPSA‐CVVH treatment lasting 8 hours each were performed. After a single session, serum total bilirubin, direct bilirubin and indirect bilirubin were significantly decreased. RRs were 52.0% ± 7.6% for total bilirubin, 59.4% ± 13.0% for direct bilirubin and 36.9% ± 15.4% for indirect bilirubin. Twenty nine patients (37.2%) survived and were discharged from the hospital, 12 of them recovered their liver function while the remaining 17 patients needed intermittent artificial liver support therapy. Conclusion: FPSA‐CVVH therapy is an effective artificial liver support therapy in patients with ALF. It may be considered as a "bridge technique" to the recovery of liver function in critical ill patients with ALF. [ABSTRACT FROM AUTHOR]