Background & Aims: Severe alcohol-related hepatitis (sAH) is an inflammatory condition with high short-term mortality. Hypothesis-driven approaches have failed to identify effective treatments. Given the role of lipids as inflammatory mediators, this study aimed to identify lipidomic changes and lipid species associated with sAH and mortality risk. Methods: Untargeted lipidomics was performed on serum samples from two cohorts of patients with sAH and decompensated cirrhosis (DC). Principal component analysis and orthogonal partial least squares discriminant analysis were used to assess lipidome changes. Correlations were made with lipoproteins, lipid mediators, cytokines, cytokeratin fragments, and histological indices. Results: In the first part, 78 patients with sAH were matched on bilirubin levels with 23 patients with DC. Lipidomics identified a distinct sAH signature involving glycerophospholipids, including PC(34:2) (odds ratio [OR] 2.18, 95% confidence interval [CI] 1.45–7.05, p = 0.01), PC(O–38:5) (OR 3.31, 95% CI 2.23–7.14, p = 0.002), PI(38:4) (OR 0.71, 95% CI 0.46–0.88, p = 0.02), and LPC(18:1) (OR 0.47, 95% CI 0.32–0.82, p = 0.01). These lipids demonstrated excellent discriminatory power between sAH and DC with areas under the receiver operating characteristic curve (AUROCs) between 0.87 and 0.88. In the second part, in 159 sAH patients, specific lipids, including carnitines CAR(2:0) (OR 2.51, 95% CI 1.25–4.96, p = 0.008) and CAR(16:1) (OR 2.21, 95% CI 1.09–7.48, p = 0.009), were linked to 90-day mortality. Acylcarnitines correlated with disease severity parameters such as model for end-stage liver disease, pro-inflammatory cytokines levels, and hepatocyte ballooning on pathology. Conclusions: Untargeted lipidomics identified a glycerophospholipid and sphingolipid signature distinguishing sAH from DC, implicating lipid species involved in liver regeneration and immune function. Acylcarnitine accumulation in patients with sAH and poor prognosis suggests mitochondrial dysfunction and warrants further investigation into therapeutic potential. Impact and implications: Lipids can act as mediators at the interface between the immune system and metabolism, potentially contributing to the pathogenesis and outcomes of patients with severe alcohol-related hepatitis, prompting us to investigate lipidomic changes in this population using untargeted approaches, compared with patients with decompensated cirrhosis. This study highlights a distinct lipidomic signature in patients with severe alcohol-related hepatitis compared with decompensated cirrhosis, primarily involving glycerophospholipids and sphingolipids. Specific lipid classes, such as acylcarnitines, suggest significant mitochondrial dysfunction and are associated with disease severity and short-term mortality in patients with severe alcohol-related hepatitis. These findings underscore the importance of targeted investigations into these lipid species, their pathways, and their links to disease severity and outcomes, particularly in this condition that currently lacks specific treatments.

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.

Background & Aims: Acute liver failure (ALF) is a life-threatening disease characterised by high-grade inflammation and immunoparesis, which is associated with a high incidence of death from sepsis. Herein, we aimed to describe the metabolic dysregulation in ALF and determine whether systemic immune responses are modulated via the lysophosphatidylcholine (LPC)-autotaxin (ATX)-lysophosphatidylcholinic acid (LPA) pathway.Methods: Ninety-six individuals with ALF, 104 with cirrhosis, 31 with sepsis and 71 healthy controls (HCs) were recruited. Pathways of interest were identified by multivariate statistical analysis of proton nuclear magnetic resonance spectroscopy and untargeted ultraperformance liquid chromatography-mass spectrometry-based lipidomics. A targeted metabolomics panel was used for validation. Peripheral blood mononuclear cells were cultured with LPA 16:0, 18:0, 18:1, and their immune checkpoint surface expression was assessed by flow cytometry. Transcript-level expression of the LPA receptor (LPAR) in monocytes was investigated and the effect of LPAR antagonism was also examined in vitro.Results: LPC 16:0 was highly discriminant between ALF and HC. There was an increase in ATX and LPA in individuals with ALF compared to HCs and those with sepsis. LPCs 16:0, 18:0 and 18:1 were reduced in individuals with ALF and were associated with a poor prognosis. Treatment of monocytes with LPA 16:0 increased their PD-L1 expression and reduced CD155, CD163, MerTK levels, without affecting immune checkpoints on T and NK/CD56+T cells. LPAR1 and 3 antagonism in culture reversed the effect of LPA on monocyte expression of MerTK and CD163. MerTK and CD163, but not LPAR genes, were differentially expressed and upregulated in monocytes from individuals with ALF compared to controls.Conclusion: Reduced LPC levels are biomarkers of poor prognosis in individuals with ALF. The LPC-ATX-LPA axis appears to modulate innate immune response in ALF via LPAR1 and LPAR3. Further investigations are required to identify novel therapeutic agents targeting these receptors.(c) 2022 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

fibrosis with high accuracy in CHB patients with NAFLD.The application of AAPHD may reduce the necessary for liver biopsy in CHB patients with NAFLD.

BackgroundIn Covid-19, profound systemic inflammatory responses are accompanied by both metabolic risk factors for severity and, separately, metabolic mechanisms have been shown to underly disease progression. It is unknown whether this reflects similar situations in sepsis or is a unique characteristic of Covid-19.AimsDefine the immunometabolic signature of Covid-19.Methods65 patients with Covid-19,19 patients with sepsis and 14 healthy controls were recruited and sampled for plasma, serum and peripheral blood mononuclear cells (PBMCs) through 10 days of critical illness. Metabotyping was performed using the Biocrates p180 kit and multiplex cytokine profiling undertaken. PBMCs underwent phenotyping by flow cytometry. Immune and metabolic readouts were integrated and underwent pathway analysis.ResultsPhopsphatidylcholines (PC) are reduced in Covid-19 but greater than in sepsis. Compared to controls, tryptophan is reduced in Covid-19 and inversely correlated with the severity of the disease and IFN-ɣ concentrations, conversely the kyneurine and kyneurine/tryptophan ratio increased in the most severe cases. These metabolic changes were consistent through 2 pandemic waves in our centre. PD-L1 expression in CD8+ T cells, Tregs and CD14+ monocytes was increased in Covid-19 compared to controls.ConclusionsIn our cohort, Covid-19 is associated with monocytopenia, increased CD14+ and Treg PD-L1 expression correlating with IFN-ɣ plasma concentration and disease severity (SOFA score). The latter is also associated with metabolic derangements of Tryptophan, LPC 16:0 and PCs. Lipid metabolism, in particular phosphatidylcholines and lysophosphatidylcolines, seems strictly linked to immune response in Covid-19. Our results support the hypothesis that IFN-ɣ -PD-L1 axis might be involved in the cytokine release syndrome typical of severe Covid-19 and the phenomenon persisted through multiple pandemic waves despite use of immunomodulation.

Background: Post-operative infection is a major cause of morbidity and mortality in Liver Transplantation (LT). Early diagnosis and antimicrobial treatment improves outcomes and ruling out sepsis aids immunosuppression decisions. Procalcitonin (PCT) has recently become part of such decision making in COVID-19 pneumonia but its role in LT is not established. We assessed the diagnostic accuracy of PCT as a diagnostic biomarker for infection or sepsis following LT. Methods: A systematic search was conducted for studies reporting diagnostic performance of PCT for infection/ sepsis following LT. Studies were assessed for reporting of diagnostic accuracy, relevance and quality.Results: Eight studies with 363 participants reported data on the diagnostic accuracy of PCT, with pooled sensitivity, specificity, diagnostic odds ratio and summary receiver operator curve of 70% (95% CI 62-78), 77% (95% CI 73-83), 15.82 (95% CI 5.82-43.12) and 0.871 respectively. There was variability in the timing of sampling (post-operative day 1-8) and range of cut-off values (0.48 to 42.8 ng/mL). Heterogeneity was reduced when only studies with adult LT recipients were considered.Conclusions: PCT performs moderately well as a diagnostic test for postoperative infection/sepsis following LT. This marker is more suited for use in adult LT populations.

abstinence rate was 104/159 (65%) (table 1).Number of patients achieving abstinence has increased following the implementation of integrated care service as shown in figure 1.

which could be partially restored by reoxygenation.

PURPOSE OF REVIEW:Present an outline of acute liver failure, from its definition to its management in critical care, updated with findings of selected newer research.RECENT FINDINGS:Survival of patients with acute liver failure has progressively improved. Intracranial hypertension complicating hepatic encephalopathy is now much less frequent than in the past and invasive ICP monitoring is now rarely used. Early renal replacement therapy and possibly therapeutic plasma exchange have consolidated their role in the treatment. Further evidence confirms the low incidence of bleeding in these patients despite striking abnormalities in standard tests of coagulation and new findings of abnormalities on thromboelastographic testing. Specific coagulopathy profiles including an abnormal vWF/ADAMTS13 ratio may be associated with poor outcome and increased bleeding risk. Use of N-acetylcysteine in nonparacetamol-related cases remains unsupported by robust clinical evidence. New microRNA-based prognostic markers to select patients for transplantation are described but are still far from widespread clinical applicability; imaging-based prognostication tools are also promising. The use of extracorporeal artificial liver devices in clinical practice is yet to be supported by evidence.SUMMARY:Medical treatment of patients with acute liver failure is now associated with significantly improved survival. Better prognostication and selection for emergency liver transplant may further improve care for these patients.

Purpose of review Present an outline of acute liver failure, from its definition to its management in critical care, updated with findings of selected newer research. Recent findings Survival of patients with acute liver failure has progressively improved. Intracranial hypertension complicating hepatic encephalopathy is now much less frequent than in the past and invasive ICP monitoring is now rarely used. Early renal replacement therapy and possibly therapeutic plasma exchange have consolidated their role in the treatment. Further evidence confirms the low incidence of bleeding in these patients despite striking abnormalities in standard tests of coagulation and new findings of abnormalities on thromboelastographic testing. Specific coagulopathy profiles including an abnormal vWF/ADAMTS13 ratio may be associated with poor outcome and increased bleeding risk. Use of N-acetylcysteine in nonparacetamol-related cases remains unsupported by robust clinical evidence. New microRNA-based prognostic markers to select patients for transplantation are described but are still far from widespread clinical applicability; imaging-based prognostication tools are also promising. The use of extracorporeal artificial liver devices in clinical practice is yet to be supported by evidence. Summary Medical treatment of patients with acute liver failure is now associated with significantly improved survival. Better prognostication and selection for emergency liver transplant may further improve care for these patients.

Purpose of review Present an outline of acute liver failure, from its definition to its management in critical care, updated with findings of selected newer research. Recent findings Survival of patients with acute liver failure has progressively improved. Intracranial hypertension complicating hepatic encephalopathy is now much less frequent than in the past and invasive ICP monitoring is now rarely used. Early renal replacement therapy and possibly therapeutic plasma exchange have consolidated their role in the treatment. Further evidence confirms the low incidence of bleeding in these patients despite striking abnormalities in standard tests of coagulation and new findings of abnormalities on thromboelastographic testing. Specific coagulopathy profiles including an abnormal vWF/ADAMTS13 ratio may be associated with poor outcome and increased bleeding risk. Use of N-acetylcysteine in nonparacetamol-related cases remains unsupported by robust clinical evidence. New microRNA-based prognostic markers to select patients for transplantation are described but are still far from widespread clinical applicability; imaging-based prognostication tools are also promising. The use of extracorporeal artificial liver devices in clinical practice is yet to be supported by evidence. Summary Medical treatment of patients with acute liver failure is now associated with significantly improved survival. Better prognostication and selection for emergency liver transplant may further improve care for these patients.

Abstract Background Sepsis and infection are the leading cause of morbidity and mortality after surgery, but the inflammatory response to the trauma of surgery can make diagnosis challenging. Carbon-13 breath delta value (13C BDV) has been shown to be discriminant as a novel diagnostic marker for sepsis and infection. We aim to assess biomarkers including BDV following major hepatopancreatobiliary (HPB) surgery to diagnose postoperative infection/sepsis. Methods 20 participants undergoing HPB surgery were recruited prospectively. Breath samples were collected from baseline preoperatively, and on postoperative days (POD) 1–9, with plasma and peripheral blood mononuclear cell (PBMC) samples preoperatively, POD1, 4 and 8. Breath samples were analysed using infrared laser spectroscopy to generate BDV (per mil). Plasma was analysed for cytokines using MesoScale Discovery immunoassay, Procalcitonin (PCT) using ELISA, and Cell surface marker expression on monocytes was phenotyped using flow cytometry. Differences between groups who did and did not develop infective complications was analysed using two-way ANOVA and Mann Whitney U test. Results 5/20 participants developed infective complications, with a mean day of diagnosis POD5. There was no difference between BDV in patients with or without infection. Monocyte count was increased in infected participants at all timepoints, and monocyte expression of PD-L1 on POD1, and CD155 and HLA-DR on POD4 was upregulated, +13.09% (95%CI 1.59 to 24.61, p<0.05), +422.5 MFI (95% CI -770.9 to -73.68, p<0.05), and +19.02% (95% CI 37.58 to 0.45, p<0.05) respectively. Conclusions Monocyte expression of PD-L1, HLA-DR and CD155 is associated with infection, +13.09% (p<0.05), +422.5 MFI (p<0.05), and +19.02% (p<0.05) respectively. The innate immune system is dysregulated in infection following major HPB surgery. In this cohort BDV did not predict infection. Further investigation of novel biomarkers including BDV and soluble monocyte markers is required.

Figure: A. OPLS-DA in positive mode.B. ROC curve of

Introduction Missed upper gastrointestinal (GI) cancers are associated with poorer survival outcomes. Missed cancer is defined as having had a negative upper GI endoscopy within three years of confirmatory diagnosis. The aims of this study are to quantify cases of missed upper GI cancer at endoscopy from a district general hospital and identify potential predisposing factors to improve future outcomes. Methods In this project, retrospective patient records were obtained from MDT meetings run between 2019 and 2020. For data comparison, similar records from previous cohorts were reviewed. The endoscopy records of these patients were extracted from the CIPTS endoscopy recording system and analysed to see if any patient had an endoscopy within the three years prior to diagnosis of their upper GI cancer. Previous endoscopies were scrutinised for the following factors: indication, visible abnormality, biopsy, endoscopist grade, sedation, presentation type, histology and follow up. Results Of the 280 patients in total, 20 (7.1%) had a negative endoscopy in three years prior to diagnosis. Subgroup analysis of 2019-20 patients showed identified 78 cases of upper GI cancer. We identified five formal cases of missed upper GI cancer in this subgroup. In the 2019-20 cohort the average age in the missed cancer group and non-missed cancer group were 83.8 and 73.2 years, respectively. Factors identified in missed cancer groups from earlier cohorts included emergency bleeding, visible abnormality not biopsied, administrative delay in rescope and lack of recognition of pathology. Conclusions The incidence of missed upper GI cancer diagnosis within this centre is similar to that of recent studies from other centres. Our study has highlighted that advanced age, accurate recognition and biopsy, and timely re-biopsy may be factors influencing missed upper GI cancers. This evidence has highlighted the importance of endoscopy training in the recognition and biopsy of pre neoplastic lesions. Furthermore, we intend to analyse data for the year 2020-21 to monitor the impact of COVID-19 on missed upper GI cancer diagnosis.