Role of Plasma Exchange and Combining Therapies in Dengue-Associated Acute Liver Failure: A Systematic Review of Individual Cases.

Background/Aims: Dengue-associated acute liver failure (ALF) poses a significant risk for mortality, especially in regions lacking access to liver transplantation. Although Plasma Exchange (PLEX) is recognized as a potential therapeutic intervention for dengue-associated ALF, data on its efficacy remain limited. This systematic review aimed to comprehensively examine the literature on PLEX and other combination therapies for dengue-associated ALF. It focused on assessing their effectiveness, safety profile, and potential implications for therapeutic interventions. Methods: In this study, we conducted a systematic review to assess the efficacy and safety of PLEX and other combination therapies in patients with dengue-associated ALF. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria were used to search the PubMed, Scopus, Embase, Ovid, and Google Scholar databases. Studies published in English between 2019 and May 2024 were included. The titles and abstracts were reviewed for discrepancies, and any differences were resolved through discussion. Results: Among the 713 studies assessed for review, 9 met the eligibility criteria. Studies have demonstrated that PLEX, both alone and in combination with other therapies, such as continuous renal replacement therapy (CRRT), improves liver function, survival rates, and neurological outcomes in patients with dengue virus. Both high- and low-volume plasma exchanges were effective. Conclusion: This systematic review highlights the beneficial role of PLEX and the potential benefits of combination therapies in the treatment of rare and severe forms of dengue-associated ALF. However, given the limited sample sizes and the necessity for well-designed studies, further investigations are needed to determine the optimal volume of PLEX and the efficacy of additional therapeutic strategies.

Adverse Events and Outcomes of High-volume Plasma Exchange in 50 Acute Liver Failure Patients: A Monocentric Retrospective Real-world Study.

Background and aims: Acute liver failure (ALF) is a condition that mostly requires Intensive Care Unit (ICU) admission and sometimes necessitates emergency liver transplantation. High-volume plasma exchange (HVPE) may improve transplant-free survival (TFS) in ALF. Our study assessed complications of HVPE therapy and outcome in ALF patients. Methods: We conducted a single-center retrospective study of all patients admitted to the ICU for ALF and who underwent HVPE between June 2016 and June 2021. The plasmapheresis technique used was centrifugation, and the volume exchanged was calculated as 15% of the ideal body weight. Dedicated staff prospectively collected clinical adverse effects, while biological data were retrospectively collected. The primary outcome was the rate of severe adverse effects (SAE, defined as severe manifestations of hypotension, allergy, metabolic disturbances or other life-threatening event) that occurred during HVPE sessions. Factors influencing day-21 TFS were also studied. Results: One hundred twenty sessions were performed in 50 patients. The main etiology for ALF was paracetamol (52% of the patients). During the session, hemoglobin, platelet, transaminases, ammonia and bilirubin decreased, coagulation factors increased, and creatinine and lactate remained unchanged. At least one SAE was reported for 32 out of 120 sessions (26.7% [19%-35.5%], mostly severe alkalosis [24/117], hypotension [4/120] and hypocalcemia [4/119]). Arterial pH ≤ 7.43 following HVPE and paracetamol etiology were negatively and positively associated with day-21 TFS, respectively. Conclusion: Severe adverse effects were frequent during HVPE performed for ALF, mainly severe alkalosis, hypotension and hypocalcemia. Post-HVPE, pH and paracetamol etiology were prognosis markers.

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

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

Overview of ferroptosis and pyroptosis in acute liver failure.

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

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

In this editorial, we comment on the article by Zhou et al. The study reveals the connection between ferroptosis and pyroptosis and the effect of silent information regulator sirtuin 1 (SIRT1) activation in acute liver failure (ALF). ALF is characterized by a sudden and severe liver injury resulting in significant hepatocyte damage, often posing a high risk of mortality. The predominant form of hepatic cell death in ALF involves apoptosis, ferroptosis, autophagy, pyroptosis, and necroptosis. Glutathione peroxidase 4 (GPX4) inhibition sensitizes the cell to ferroptosis and triggers cell death, while Gasdermin D (GSDMD) is a mediator of pyroptosis. The study showed that ferroptosis and pyroptosis in ALF are regulated by blocking the p53/GPX4/GSDMD pathway, bridging the gap between the two processes. The inhibition of p53 elevates the levels of GPX4, reducing the levels of inflammatory and liver injury markers, ferroptotic events, and GSDMD-N 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.

Role of therapeutic plasmapheresis in acute liver failure in paediatric patients: A case series.

Paediatric acute liver failure (PALF) is a rare yet severe condition that is associated with high mortality. Apart from liver transplant, no specific therapy exists, particularly in developing countries. Evidence suggests that removal of damage-associated molecular patterns, cytokines, toxins, and other metabolites that accumulate due to impaired liver function can enhance natural recovery. Plasmapheresis can be used to remove these products; however, there is limited evidence to support this approach. This case series discusses three critically ill patients with acute liver failure who underwent plasmapheresis. The patients included a seven-year-old boy (Case 1), a 17-year-old boy (Case 2), and a 16-monthold boy (Case 3). Two patients showed significant improvement in bilirubin level, coagulation profile, inotropes requirement, and Glasgow coma scale score. Unfortunately, one patient with PALF, complicated with multi-organ dysfunction, died due to refractory shock on the fourth day of hospitalisation. Our findings illustrate that early use of therapeutic plasmapheresis in PALF can lead to improvement in clinical outcome. It may serve as a bridging therapy for liver transplant and for the spontaneous regeneration of the patient's liver.

Long-term expanded hepatic progenitor cells ameliorate D-GalN/LPS-induced acute liver failure through repolarizing M1 macrophage to M2-Like phenotype via activation of the IL-10/JAK2/STAT3 signaling pathway.

Acute liver failure (ALF) is a devastating liver disease characterized by the rapid deterioration of hepatocytes, which causes a series of clinical complications, including hepatic dysfunction, coagulopathy, encephalopathy, and multiorgan failure. Cell-based therapy is a promising alternative as it can bridge patients until their livers regenerate, releasing immunomodulatory molecules to suppress inflammation. This study reports an iPSCs-derived long-term expanded hepatic progenitor cell (LTHepPCs), which can differentiate into hepatocyte-like cells (HLCs) in vivo. When introduced into drug-induced ALF models, LTHepPCs mitigate liver damage by modulating the local immune microenvironment. This is achieved by shifting macrophages/Kupffer cells towards an anti-inflammatory state, resulting in a decrease in the expression of inflammatory cytokines such as TNF-a, IL-1ß, and IL-8, and an increase in the expression of anti-inflammatory cytokines such as IL-10 and ARG-1. In vitro co-culturing of THP-1 or mBMDMs with LTHepPCs suggested that LTHepPCs could activate the anti-inflammatory state of macrophages/Kupffer cells via the IL-10/JAK2/STAT3 signaling pathway. Therefore, LTHepPC transplantation is a promising therapy for ALF patients.

Systemic T-cell activation and interferon-γ activity in indeterminate severe hepatitis (iSH) are reminiscent of hemophagocytic lymphohistiocytosis (HLH): Implications for T-cell and interferon-γ directed therapies.

BACKGROUND: Severe hepatitis cases in children are increasingly recognized, however, the exact etiology remains unknown in a significant proportion of patients. Cases of indeterminate severe hepatitis (iSH) may progress to indeterminate pediatric acute liver failure (iPALF), hence understanding the immunobiology is critical to preventing disease progression. Hemophagocytic lymphohistiocytosis (HLH) is a systemic hyperinflammatory disorder associated with T-cell and macrophage activation with liver injury. OBJECTIVES: We hypothesized a high proportion of patients with iSH demonstrate systemic T-cell activation similar to HLH prior to developing iPALF and that the degree of T-cell activation in iSH might correlate with outcomes. METHODS: From 2019-2022, 14 patients with iSH and 7 patients with PALF of known, non-immune etiology were prospectively enrolled. We compared immune signatures of iSH, HLH, known PALF, and healthy controls. RESULTS: We found that patients with iSH have increased CD8+ T-cell activation and high interferon-γ activity similar to HLH. The amplitude of CD8+ T-cell activation was predictive of iSH progression to iPALF. We also found that in patients with iSH, ferritin had only modest elevation. However, age-normalized plasma soluble interleukin-2 receptor (sIL-2R) to ferritin level ratio can distinguish iSH from known PALF and HLH. As a proof of concept, we report that in three patients with steroid refractory iSH, emapalumab, an IFN-γ blocking antibody used in combination with steroids, improved liver function and may have prevented progression to PALF. CONCLUSIONS: Our data suggests flow-based T-cell activation markers could help in early identification and risk stratification for targeted intervention in patients with iSH.

Association between systemic immune inflammation index and short term prognosis of acute on chronic liver failure.

The systemic immune-inflammatory index (SII) has been identified as an independent prognostic factor for multiple diseases. However, the impact of SII on outcome of acute-on-chronic liver failure (ACLF) is scant. A retrospective study enrolled patients with ACLF treated with artificial liver support system. Restricted cubic spline (RCS) (knots at the 10th, 50th, and 90th percentiles) and Cox proportional hazards models were applied to investigate the relationship between SII and 90-day transplant-free survival and overall survival in patients with ACLF. A total of 258 patients with ACLF were included. The 90-day transplant-free survival rate and overall survival rate were 58.5% and 66.3%. The SII was 465.5 (277.3-804.4). Adjusted RCS models showed linear exposure-response relationship between SII and 90-day transplant-free survival (P for overall < 0.001, P for nonlinear = 0.154) and 90-day overall survival (P for overall < 0.001, P for nonlinear = 0.103), and adjusted Cox models confirmed the positive relationship. Compared with patients with SII < 480, patients with ≥ 480 had more serious  condition, lower 90-day transplant-free survival rate (46.8% vs. 69.7%, adjusted HR (95% CI) for transplant or death: 2.13 (1.40-3.23), P < 0.001), and lower 90-day overall survival rate (56.3% vs. 75.8%; adjusted HR (95% CI) for death: 2.26 (1.42-3.61), P = 0.001). Stratified Cox models suggested no potential modifiers in the relationship between SII and 90-day transplant-free survival. Our findings suggested SII was positively associated with poor short-term prognosis of ACLF.

Clinical significance and outcomes of adult living donor liver transplantation for acute liver failure: a retrospective cohort study based on 15-year single-center experience.

Purpose: This study aimed to describe adult living donor liver transplantation (LDLT) for acute liver failure and evaluate its clinical significance by comparing its surgical and survival outcomes with those of deceased donor liver transplantation (DDLT). Methods: We retrospectively reviewed the medical records of 267 consecutive patients (161 LDLT recipients and 106 DDLT recipients) aged 18 years or older who underwent liver transplantation between January 2006 and December 2020. Results: The mean periods from hepatic encephalopathy to liver transplantation were 5.85 days and 8.35 days for LDLT and DDLT, respectively (P = 0.091). Among these patients, 121 (45.3%) had grade III or IV hepatic encephalopathy (living, 34.8% vs. deceased, 61.3%; P < 0.001), and 38 (14.2%) had brain edema (living, 16.1% vs. deceased, 11.3%; P = 0.269) before liver transplantation. There were no significant differences in in-hospital mortality (living, 11.8% vs. deceased, 15.1%; P = 0.435), 10-year overall survival (living, 90.8% vs. deceased, 84.0%; P = 0.096), and graft survival (living, 83.5% vs. deceased, 71.3%; P = 0.051). However, postoperatively, the mean intensive care unit stay was shorter in the LDLT group (5.0 days vs. 9.5 days, P < 0.001). In-hospital mortality was associated with vasopressor use (odds ratio [OR], 3.40; 95% confidence interval [CI], 1.45-7.96; P = 0.005) and brain edema (OR, 2.75; 95% CI, 1.16-6.52; P = 0.022) of recipient at the time of transplantation. However, LDLT (OR, 1.26; 95% CI, 0.59-2.66; P = 0.553) was not independently associated with in-hospital mortality. Conclusion: LDLT is feasible for acute liver failure when organs from deceased donors are not available.

Comparative Mortality Rates of Vasoconstrictor Agents in the Management of Hepatorenal Syndrome: A Systematic Review and Meta-Analysis.

Hepatorenal syndrome (HRS) is an acute complication of advanced liver disease, which manifests with a rapidly progressive decline in kidney function. Though pharmacological treatment has been recently advanced, there are still high mortality rates. The study compares the mortality rate in patients using different vasoconstrictor agents in the management of HRS. A complete literature search was done in the following databases: PubMed, Cochrane Library, PubMed Central (PMC), and Multidisciplinary Digital Publishing Institute (MDPI). Studies were included according to previously established criteria, in which all studies reporting on adult patients with HRS treated with vasoconstrictor agents were eligible. The data extracted were analyzed with a random-effects model to express variability between studies, and the principal measure was the risk ratio (RR) for mortality. Of the 8,137 studies identified, 29 met the inclusion criteria. In the meta-analysis, vasoconstrictors, mainly terlipressin, significantly improved renal function and decreased the need for renal replacement therapy (RRT) versus placebo. However, a significant impact on mortality was lacking (0.94 (0.84-1.06), p = 0.31). The subgroup analysis found that mortality rates were not significantly different between vasoconstrictors, whether used in combination with or without albumin (0.97 (0.77-1.23), p = 0.79, and 0.98 (0.79-1.21), p = 0.86). Global heterogeneity was low, indicating consistent results in the studies. Vasoconstrictors are helpful in managing HRS, with improvement in renal function and reduction in RRT requirements. However, the effect on mortality was small and nonsignificant. Such findings support the use of terlipressin in HRS management; concomitantly, they emphasize the need for personalized treatment strategies and future research to find alternative therapies that may be more effective for improved survival results with fewer side effects.

Metastatic melanoma: an unexpected cause of acute liver failure.

Acute liver failure secondary to metastatic melanoma is exceedingly rare with the literature limited to case reports. The disease itself presents with vague symptoms making diagnosis difficult without a high clinical suspicion. Further to this, the prognosis of acute liver failure secondary to metastatic melanoma is dismal. We present the case of a 59-year-old male with a distant history of previously excised cutaneous melanoma who presented to our institution with abdominal pain and liver enzyme derangement suggestive of acute hepatitis. Due to progressive derangement in liver function and cross-sectional imaging suggestive of an infiltrative cause, a left axillary lymph node was biopsied which demonstrated metastatic melanoma. The patient subsequently deteriorated into acute liver failure and despite acute treatment of his underlying metastatic melanoma died 17 days post initial presentation. This case highlights an uncommon cause of acute liver failure as well as the poor prognosis associated with acute liver failure secondary to metastatic melanoma.

Acute Liver Failure Induced by Provitalize: A Menopause Supplement Concocted From Herbs & Probiotics.

Drug-induced liver injury is one of the most common causes of acute liver failure in the Western world. Despite discontinuation of the offending agent, it can still tax a grim prognosis. We describe a case of a menopausal woman taking a herbal supplement called "Provitalize" to relieve hot flashes and bloating. This is the first case report of liver injury from this supplement. She initially presented with mild jaundice and elevated transaminases. Unfortunately, she rapidly progressed to encephalopathy, experienced multiorgan failure, and then died.

Syphilitic hepatitis in infants, the forgotten disease that hepatologists have to brush up on: from a case series to a revision of literature.

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.

Home-based EXercise and motivAtional programme before and after Liver Transplantation (EXALT): study protocol for phase II two-centre, randomised controlled trial.

INTRODUCTION: Physical frailty is associated with increased mortality and poor quality of life (QoL) before and after liver transplantation (LT). Evidence is lacking on how to tailor exercise and behavioural techniques in this patient population. METHODS AND ANALYSIS: Home-based EXercise and motivAtional programme before and after Liver Transplantation (EXALT) is a phase 2b, open-label, two-centre randomised controlled clinical trial designed to investigate whether a remotely monitored 'home-based exercise and theory-based motivation support programme (HBEP)' before and after LT improves QoL in LT recipients. Adult patients awaiting a primary LT will be assessed for eligibility at two LT centres (Birmingham, Royal Free London). Participants will be randomly assigned (1:1) to receive either an HBEP while on the LT waiting list through to 24 weeks after LT (Intervention) or a patient exercise advice leaflet (Control). Using a standard method of difference in means (two-sided significance level 0.05; power 0.90) and accounting for a 35% attrition/withdrawal rate, a minimum of 133 patients will be randomised to each treatment group. The primary outcome measure will be assessed using intention-to-treat analysis of the difference in the Physical Component Score of Short form-36 version 2.0 health-related QoL questionnaire between the groups at 24 weeks post-LT. ETHICS AND DISSEMINATION: The protocol was approved by the South Central-Hampshire A National Research Ethics Committee. Recruitment into the EXALT trial started in May 2022 and is due to end in June 2024, with 217/266 patients randomised to date. The intervention follow-up is due to finish in May 2026. The findings of this trial will be disseminated through peer-reviewed publications, conferences and social media. TRIAL REGISTRATION NUMBER: ISRCTN13476586.

The Impact of Liver Failure on the Immune System.

Liver failure profoundly affects the immune system, leading to dysregulation of innate and adaptive immune response. This review explores the intricate relationship between liver function and immune homeostasis. The role of the liver as a central hub in immune response initiation is elucidated, emphasizing its involvement in hepatic inflammation induction and subsequent systemic inflammation. Cytokines, chemokines, growth factors, and lipid mediators orchestrate these immune processes, serving as both prognostic biomarkers and potential therapeutic targets in liver failure-associated immune dysregulation, which might result from acute-on-chronic liver failure (ACLF) and cirrhosis. Furthermore, the review delves into the mechanisms underlying immunosuppression in liver failure, encompassing alterations in innate immune cell functions such as neutrophils, macrophages, and natural killer cells (NK cells), as well as perturbations in adaptive immune responses mediated by B and T cells. Conclusion: Understanding the immunological consequences of liver failure is crucial for developing targeted therapeutic interventions and improving patient outcomes in liver disease management.

High bone fracture risk in a large modern cohort of liver transplant recipients.

Liver transplantation (LT) has historically been associated with a high prevalence of osteoporosis, but most of the available data date back to late 1990s-early 2000s with limited sample size. Our aim was to assess the prevalence of bone fragility fractures and contributing factors in a large modern cohort of liver transplant recipients. Retrospective study of 429 consecutive patients receiving liver transplantation from 1/1/2010 to 31/12/2015. Final cohort included 366 patients. Electronic radiological images (lateral views of spine X-rays or Scout CT abdominal scans) performed within 6 months from LT, were blinded reviewed to screen for morphometric vertebral fractures. Symptomatic clinical fragility fractures were recorded from the medical records. Patients with fragility fractures in the cohort were 155/366 (42.3%), with no significant differences between sexes. Most sustained vertebral fractures (145/155, 93.5%), mild or moderate wedges, with severe fractures more frequently observed in women. Multiple vertebral fractures were common (41.3%). Fracture rates were similar across different etiologies of cirrhosis and independent of diabetes or glucocorticoids exposure. Kidney function was significantly worse in women with fractures. Independently of age, sex, alcohol use, eGFR, and etiology of liver disease, low BMI was significantly associated with an increased risk for fractures (adjusted OR 1.058, 95%CI 1.001-1.118, P = 0.046). Our study shows a considerable fracture burden in a large and modern cohort of liver transplant recipients. Given the very high prevalence of bone fractures, a metabolic bone disease screening should be implemented in patients awaiting liver transplantation.

Neutrophil Extracellular Trap Scores Predict 90-Day Mortality in Hepatitis B-Related Acute-on-Chronic Liver Failure.

Hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) is associated with pronounced systemic inflammation, and neutrophil extracellular traps (NETs) are key components of this response. The primary objective of this study was to establish an NET-related scoring system for patients with HBV-ACLF. A prospective training cohort of 81 patients from the Beijing Ditan Hospital was included. The concentrations of NET markers (cell-free DNA, myeloperoxidase DNA [MPO-DNA], and citrullinated histone H3) in peripheral blood were quantified. Random survival forest, LASSO regression, and multivariate Cox regression analyses were used to identify prognostic factors associated with 90-day mortality in ACLF patients and develop a nomogram for visualization, which was followed by evaluation in a validation cohort (n = 40). NET-related marker levels were significantly higher in the non-survival group than in the survival group (p < 0.05). The NET score was constructed by combining MPO-DNA, neutrophil-to-lymphocyte ratio, and age data. The score's diagnostic effectiveness, assessed by the area under the curve, yielded values of 0.83 and 0.77 in the training and validation sets, respectively, markedly surpassing those of other established models (p < 0.05). In both groups, the 90-day mortality rates were 88.8% and 75.0%, respectively, for patients categorized as high risk and 18.0% and 12.5%, respectively, for those classified as low risk.

Hepatic and extrahepatic metabolic modulation in hbv-related decompensated cirrhosis and acute-on-chronic liver failure.

Acute-on-chronic liver failure (ACLF) and decompensated cirrhosis (DC) are life-threatening syndromes that can develop at the end-stage of chronic hepatitis B virus (HBV) infection. Both ACLF and DC are complicated by hepatic and extrahepatic pathogeneses. To better understand the compartment-specific metabolic modulations related to their pathogenesis, HBV-DC, HBV-ACLF patients, and controls (30 each) were analyzed by metabolomics using portal (Port), hepatic vein (Hep), and peripheral (Peri) serum. Compartment ratios of metabolites (RatioHep/Port, RatioPeri/Hep, and RatioPort/Peri) were calculated. The liver tissues (10 per group) were analyzed using transcriptomics and metabolomics. An additional 75 patients with ACLF, 20 with DC, and 20 with liver cirrhosis (LC) were used to confirm oxlipid dysregulation. Both multi-omics datasets suggest suppressed energy, amino acid, and pyrimidine metabolism in the ACLF/DC liver. The serum metabolomic variations were contributed primarily by disease rather than sampling compartments, as both HBV-ACLF and HBV-DC patients demonstrated abnormal profiles of amino acids and peptides, indoles, purines, steroids, and benzimidazoles. In ACLF/DC patients, impaired hepatic metabolism resulted in a highly correlated hepatic and portal vein serum metabolome and release of inflammatory lipids and heme metabolites from the liver. HBV-ACLF showed higher RatioPeri/Hep of extrahepatic inflammatory oxlipids, while HBV-DC patients showed higher RatioPort/Peri of gut microbial metabolites. An inflammatory oxlipid outburst was confirmed in the early stages of HBV-ACLF. The inflammatory effects of the selected oxlipids were confirmed in monocytes. These findings support a synergy between liver-specific mechanisms and systemic inflammation in ACLF/DC development, and that pro-inflammatory oxlipids are metabolic signatures of early HBV-ACLF.

Is there a role for extracorporeal membrane oxygenation in children with acute liver failure? A retrospective analysis of the Extracorporeal Life Support Organization Registry.

Data describing the use of extracorporeal membrane oxygenation (ECMO) in pediatric acute liver failure (PALF) are scarce. Thus, we aimed to describe the use of ECMO in patients with PALF using the data from the Extracorporeal Life Support Organization (ELSO) Registry between January 1, 2010, to December 31, 2022. We described patients' characteristics at ECMO initiation, outcome, and factors associated with mortality. A total of 335 children underwent ECMO support in the context of PALF. Veno-arterial (VA) ECMO was the most prevalent mode (66.6%), followed by veno-venous (VV) ECMO (33.4%). Extracorporeal cardiopulmonary resuscitation (ECPR) was used in 21.5% of the cardiac arrest. In-hospital mortality was 66.6%. Both higher lactate (OR 1.128, CI 1.06-1.209, p < 0.001) and PaCO2 (OR 1.022, CI 1.001-1.047, p 0.05) levels before ECMO reported greater odds of mortality. Low body weight, persistence of hyperlactatemia (OR 0.985, CI 0.973-0.997, p 0.013), and hyperbilirubinemia (OR 2.477, CI 1.042-6.100, p 0.045) after 24 h from ECMO deployment were associated to greater odds of mortality. CONCLUSIONS: Our results suggest that the use of ECMO for the management of respiratory and cardiac failure in patients with PALF should be considered with caution and that further research is needed to understand its role in this specific high-risk population. WHAT IS KNOWN: • Pediatric acute liver failure (PALF) is a clinical syndrome associated with significant morbidity and mortality. • Data on the use of extracorporeal membrane oxygenation (ECMO) in the context of PALF are scarce and controversial. WHAT IS NEW: • ECMO to manage acute respiratory and/or cardiac failure in the context of PALF should be considered with caution. • Bleeding and thrombotic complications in children with acute liver failure receiving ECMO are similar to the ones reported in the general pediatric population.