Congruent identification of imbalanced fibrinolysis by 2 distinct clot lysis time assays.

Background: A plasma-based clot lysis time (CLT) assay is an established research test to assess plasma fibrinolytic potential, with application in hyperfibrinolytic or hypofibrinolytic conditions. Interprotocol variations make comparisons between laboratories challenging. The aim of this study was to compare the results of 2 different CLT assays performed by 2 distinct research laboratories by using their own protocol. Methods: We evaluated fibrinolysis in the plasma of 60 patients undergoing hepatobiliary surgery and in plasma from a healthy donor that was spiked with commonly used anticoagulant drugs (enoxaparin, dabigatran, and rivaroxaban) in 2 distinct laboratories (Aarhus and Groningen) by using 2 different assays that differ, among others, in tissue plasminogen activator (tPA) concentration. Results: Overall conclusions on fibrinolytic potential in patients undergoing hepatobiliary surgery were similar between the 2 CLT assays, with hyperfibrinolytic and hypofibrinolytic profiles identified at the same time points during and after surgery. Severe hypofibrinolysis was less commonly reported in the Aarhus assay (36/319 samples; 11%) than in the Groningen assay (55/319 samples; 17%). No clot formation was observed in 31 of 319 samples in the Aarhus assay vs 0 of 319 samples in the Groningen assay. Clotting times increased much more profoundly on the addition of all 3 anticoagulants in the Aarhus assay. Conclusions: Despite the differences in laboratory, protocol, reagents, operator, data processing, and analysis, overall conclusions on fibrinolytic capacity are similar between the 2 laboratories. With a higher concentration of tPA in the Aarhus assay, the test becomes less sensitive for the detection of hypofibrinolysis and is more sensitive to the addition of anticoagulants.

Lysophosphatidylcholines modulate immunoregulatory checkpoints in peripheral monocytes and are associated with mortality in people with acute liver failure.

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. IMPACT AND IMPLICATIONS: We identified a metabolic signature of acute liver failure (ALF) and investigated the immunometabolic role of the lysophosphatidylcholine-autotaxin-lysophosphatidylcholinic acid pathway, with the aim of finding a mechanistic explanation for monocyte behaviour and identifying possible therapeutic targets (to modulate the systemic immune response in ALF). At present, no selective immune-based therapies exist. We were able to modulate the phenotype of monocytes in vitro and aim to extend these findings to murine models of ALF as a next step. Future therapies may be based on metabolic modulation; thus, the role of specific lipids in this pathway require elucidation and the relative merits of autotaxin inhibition, lysophosphatidylcholinic acid receptor blockade or lipid-based therapies need to be determined. Our findings begin to bridge this knowledge gap and the methods used herein could be useful in identifying therapeutic targets as part of an experimental medicine approach.

Inpatient COVID-19 mortality has reduced over time: Results from an observational cohort.

BACKGROUND: The Covid-19 pandemic in the United Kingdom has seen two waves; the first starting in March 2020 and the second in late October 2020. It is not known whether outcomes for those admitted with severe Covid were different in the first and second waves. METHODS: The study population comprised all patients admitted to a 1,500-bed London Hospital Trust between March 2020 and March 2021, who tested positive for Covid-19 by PCR within 3-days of admissions. Primary outcome was death within 28-days of admission. Socio-demographics (age, sex, ethnicity), hypertension, diabetes, obesity, baseline physiological observations, CRP, neutrophil, chest x-ray abnormality, remdesivir and dexamethasone were incorporated as co-variates. Proportional subhazards models compared mortality risk between wave 1 and wave 2. Cox-proportional hazard model with propensity score adjustment were used to compare mortality in patients prescribed remdesivir and dexamethasone. RESULTS: There were 3,949 COVID-19 admissions, 3,195 hospital discharges and 733 deaths. There were notable differences in age, ethnicity, comorbidities, and admission disease severity between wave 1 and wave 2. Twenty-eight-day mortality was higher during wave 1 (26.1% versus 13.1%). Mortality risk adjusted for co-variates was significantly lower in wave 2 compared to wave 1 [adjSHR 0.49 (0.37, 0.65) p<0.001]. Analysis of treatment impact did not show statistically different effects of remdesivir [HR 0.84 (95%CI 0.65, 1.08), p = 0.17] or dexamethasone [HR 0.97 (95%CI 0.70, 1.35) p = 0.87]. CONCLUSION: There has been substantial improvements in COVID-19 mortality in the second wave, even accounting for demographics, comorbidity, and disease severity. Neither dexamethasone nor remdesivir appeared to be key explanatory factors, although there may be unmeasured confounding present.

[ESPEN Practical Guideline: clinical nutrition in liver disease]. / Guía Práctica ESPEN: nutrición clínica en las enfermedades del hígado.

Introduction: Background: the Practical Guideline is based on the current scientific ESPEN guide on Clinical Nutrition in Liver Disease. Methods: it has been shortened and transformed into flow charts for easier use in clinical practice. The guideline is dedicated to all professionals including physicians, dieticians, nutritionists and nurses working with patients with chronic liver disease. Results: a total of 103 statements and recommendations are presented with short commentaries for the nutritional and metabolic management of patients with (i) acute liver failure, (ii) alcoholic steatohepatitis, (iii) non-alcoholic fatty liver disease, (iv) liver cirrhosis, and (v) liver surgery/transplantation. Disease-related recommendations are preceded by general recommendations on the diagnosis of nutritional status in liver patients and on liver complications associated with medical nutrition. Conclusion: this Practical Guideline gives guidance to health care providers involved in the management of liver disease on how to offer optimal nutritional care.

Introducción: Introducción: la Guía Práctica se basa en la actual guía científica de la ESPEN sobre nutrición clínica en las enfermedades hepáticas. Métodos: se ha reducido y transformado en diagramas de flujo para facilitar su uso en la práctica clínica. La guía está dedicada a todos los profesionales, incluidos médicos, dietistas, nutricionistas y enfermeras, que trabajan con pacientes con enfermedad hepática crónica. Resultados: la guía presenta un total de 103 pronunciamientos y recomendaciones con breves comentarios para el manejo nutricional y metabólico de pacientes con (i) insuficiencia hepática aguda grave, (ii) esteatohepatitis alcohólica, (iii) enfermedad hepática grasa no alcohólica, (iv) cirrosis hepática, y (v) cirugía o trasplante de hígado. Conclusión: las recomendaciones relacionadas con enfermedades están precedidas por recomendaciones generales sobre el diagnóstico del estado nutricional en los pacientes hepáticos y sobre las complicaciones hepáticas asociadas a la nutrición médica.

Prevalence of Bleeding and Thrombosis in Critically Ill Patients with Chronic Liver Disease.

INTRODUCTION: Hemorrhage and venous thromboembolism (VTE) are recognized complications of chronic liver disease (CLD), but their prevalence and risk factors in critically ill patients are uncertain. PATIENTS AND METHODS: We studied a retrospective cohort of patients with CLD nonelectively admitted to a specialist intensive care unit (ICU) determining the prevalence and timing of major bleeding and VTE (early, present on admission/diagnosed within 48 hours; later, diagnosed >48 hours post-ICU admission). Associations with baseline clinical and laboratory characteristics, multiorgan failure (MOF), blood product administration, and mortality were explored. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression. RESULTS: Of 623 patients with median age 52, bleeding (>48 hours after admission) occurred in 87 (14%) patients. Bleeding was associated with greater illness severity and increased mortality. Gastrointestinal bleeding accounted for 72% of events, secondary to portal hypertension in >90%. Procedure-related bleeding was uncommon. VTE occurred in 125 (20%) patients: early VTE in 80 (13%) and involving the portal vein in 85%. Later VTE affected 45 (7.2%) patients. Hepatocellular carcinoma (HCC) and nonalcoholic liver disease were independently associated with early VTE (OR: 2.79, 95% CI: 1.5-5.2 and OR: 2.32, 95% CI: 1.4-3.9, respectively), and HCC, sepsis, and cryoprecipitate use with late VTE (OR: 2.45, 95% CI: 1.11-5.43; OR: 2.26, 95% CI: 1.2-4.3; and OR: 2.60, 95% CI: 1.3-5.1). CONCLUSION: VTE was prevalent on admission to critical care and less commonly developed later. Bleeding was associated with MOF and increased mortality. Severe MOF was not associated with an increased rate of VTE which was linked with HCC, and specific etiologies of CLD.

The Impact of Performance Status on Length of Hospital Stay and Clinical Complications Following Liver Transplantation.

BACKGROUND: Impaired pretransplant performance status (PS) is associated with chronic liver disease (CLD). We studied its impact on hospital length of stay (LOS), complications, and readmissions in the first year after liver transplantation. METHODS: The Standard National Liver Transplant Registry was linked to a hospital administrative dataset, and all first-time liver transplant recipients with CLD aged ≥18 years in England were identified. A modified 3-level Eastern Cooperative Oncology Group score was used to assess PS. Linear- and logistic-fixed effect regression models were used to estimate the effect of specific posttransplant complications and readmissions in the first year after transplantation. RESULTS: Six thousand nine hundred sixty-eight recipients were included. Impaired PS was associated with an increased LOS in the initial posttransplant period (comparing ECOG 1-3, adjusted difference 7.2 d; 95% confidence [CI], 4.8-9.6; P < 0.001) and in time spent on the ITU (adjusted difference 1.2 d; 95% CI, 0.4-2.0; P < 0.001). There was no significant association between ECOG status and total LOS of later admissions (adjusted difference, 2.5 d; 95% CI, -0.4-5.5; P = 0.23). Those with a poorer ECOG status had an increased incidence of renal failure (odds ratio, 1.5; 95% CI, 1.1-2.0; P = 0.004) and infection (odds ratio, 1.2; 95% CI, 1.1-1.4; P = 0.02) but not an increased incidence of readmission (odds ratio, 1.2; 95% CI, 0.9-1.5; P = 0.13). CONCLUSIONS: In liver transplant recipients with CLD, impaired pretransplant PS is associated with prolonged LOS in the immediate posttransplant period but not with LOS of later admissions in the first year after transplantation. Impaired PS increased the risk of renal failure and infection.

ESPEN practical guideline: Clinical nutrition in liver disease.

BACKGROUND: The Practical guideline is based on the current scientific ESPEN guideline on Clinical Nutrition in Liver Disease. METHODS: It has been shortened and transformed into flow charts for easier use in clinical practice. The guideline is dedicated to all professionals including physicians, dieticians, nutritionists and nurses working with patients with chronic liver disease. RESULTS: A total of 103 statements and recommendations are presented with short commentaries for the nutritional and metabolic management of patients with (i) acute liver failure, (ii) alcoholic steatohepatitis, (iii) non-alcoholic fatty liver disease, (iv) liver cirrhosis, and (v) liver surgery/transplantation. The disease-related recommendations are preceded by general recommendations on the diagnostics of nutritional status in liver patients and on liver complications associated with medical nutrition. CONCLUSION: This practical guideline gives guidance to health care providers involved in the management of liver disease to offer optimal nutritional care.

Efficacy of pro- and anticoagulant strategies in plasma of patients undergoing hepatobiliary surgery.

BACKGROUND: In vitro efficacy of pro- and antihemostatic drugs is profoundly different in patients with compensated cirrhosis and in those who have cirrhosis and are critically ill. OBJECTIVES: Here we assessed the efficacy of pro- and anticoagulant drugs in plasma of patients undergoing hepato-pancreato-biliary (HPB) surgery, which is associated with unique hemostatic changes. METHODS: We performed in vitro analyses on blood samples of 60 patients undergoing HPB surgery and liver transplantation: 20 orthotopic liver transplantations, 20 partial hepatectomies, and 20 pylorus-preserving pancreaticoduodenectomies. We performed thrombin generation experiments before and after in vitro addition of fresh frozen plasma (FFP), prothrombin complex concentrate (PCC), recombinant factor VIIa (rFVIIa), low molecular weight heparin (LMWH), unfractionated heparin, dabigatran, and rivaroxaban. RESULTS: We showed that patients undergoing HPB surgery are in a hypercoagulable state by thrombin generation testing. FFP and rFVIIa had minimal effects on thrombin generation, whereas PCC had a more pronounced procoagulant effect in patients compared with controls. Dabigatran showed a more pronounced anticoagulant effect in patients compared with controls, whereas rivaroxaban and LMWH had a decreased anticoagulant effect in patients. CONCLUSION: We demonstrate profoundly altered in vitro efficacy of commonly used anticoagulants, in patients undergoing HPB surgery compared with healthy controls, which may have implications for anticoagulant dosing in the early postoperative period. In the correction of perioperative bleeding complications, PCCs appear much more potent than FFP or rFVIIa, and PCCs may require conservative dosing and caution in use in patients undergoing HPB surgery.

Sequential Cohort Analysis After Liver Transplantation Shows de Novo Extended Release Tacrolimus Is Safe, Efficacious, and Minimizes Renal Dysfunction.

The use of once-daily extended-release tacrolimus (ERT) is associated with improved long-term graft and patient survival when compared with twice-daily tacrolimus (BDT), but the underlying reasons for differential survival are unclear. The aim of the study was to compare clinical outcomes known to impact on posttransplant survival for de novo BDT and ERT in liver transplantation (LT) recipients. METHODS: We conducted a single-center, prospective sequential cohort analysis of adult patients undergoing LT during a change in protocol from de novo BDT to ERT, with a 6-month post-LT follow-up. RESULTS: A total of 160 transplanted patients were evaluated; 82 were in the BDT group and 78 were in the ERT group. The cohorts were matched for standard variables and a similar proportion in each group received induction interleukin-2 receptor antibody (36% and 31%). There were no significant differences in the measured outcomes of patient and graft survival, biopsy-proven acute rejection episodes, post LT diabetes, and toxicity. A significantly lower number of patients developed chronic kidney disease Stage3-4 in the ERT cohort compared with BDT cohort. In patients with pre-LT renal dysfunction who received antibody induction, estimated glomerular filtration rate decreased significantly in the BDT but not the ERT group. CONCLUSIONS: We show that once-daily ERT is as safe and efficacious as BDT in de novo LT but optimally conserves renal function post-LT.

Assessing the Time-Dependent Impact of Performance Status on Outcomes After Liver Transplantation.

BACKGROUND AND AIMS: Identifying how the prognostic impact of performance status (PS) differs according to indication, era, and time period ("epoch") after liver transplantation (LT) could have implications for selection and treatment of patients on the waitlist. We used national data from the United Kingdom and Ireland to assess impact of PS on mortality separately for HCC and non-HCC recipients. APPROACH AND RESULTS: We assessed pre-LT PS using the 5-point modified Eastern Cooperative Oncology Group scale and used Cox regression methods to estimate hazard ratios (HRs) that compared posttransplantation mortality in different epochs of follow-up (0-90 days and 90 days to 1 year) and in different eras of transplantation (1995-2005 and 2006-2016). 2107 HCC and 10,693 non-HCC patients were included. One-year survival decreased with worsening PS in non-HCC recipients where 1-year survival was 91.9% (95% confidence interval [CI], 88.3-94.4) in those able to carry out normal activity (PS1) compared to 78.7% (95% CI, 76.7-80.5) in those completely reliant on care (PS5). For HCC patients, these estimates were 89.9% (95% CI, 85.4-93.2) and 83.1% (95% CI, 61.0-93.3), respectively. Reduction in survival in non-HCC patients with poorer PS was in the first 90 days after transplant, with no major effect observed between 90 days and 1 year. Adjustment for donor and recipient characteristics did not change the findings. Comparing era, post-LT mortality improved for HCC (adjusted HR, 0.55; 95% CI, 0.40-0.74) and non-HCC recipients (0.48; 95% CI, 0.42-0.55), but this did not differ according to PS score (P = 0.39 and 0.61, respectively). CONCLUSIONS: Impact on mortality of the recipient's pretransplant PS is principally limited to the first 3 months after LT. Over time, mortality has improved for both HCC and non-HCC recipients and across the full range of PS.

Blood metabolomics uncovers inflammation-associated mitochondrial dysfunction as a potential mechanism underlying ACLF.

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF), which develops in patients with cirrhosis, is characterized by intense systemic inflammation and organ failure(s). Because systemic inflammation is energetically expensive, its metabolic costs may result in organ dysfunction/failure. Therefore, we aimed to analyze the blood metabolome in patients with cirrhosis, with and without ACLF. METHODS: We performed untargeted metabolomics using liquid chromatography coupled to high-resolution mass spectrometry in serum from 650 patients with AD (acute decompensation of cirrhosis, without ACLF), 181 with ACLF, 43 with compensated cirrhosis, and 29 healthy individuals. RESULTS: Of the 137 annotated metabolites identified, 100 were increased in patients with ACLF of any grade, relative to those with AD, and 38 comprised a distinctive blood metabolite fingerprint for ACLF. Among patients with ACLF, the intensity of the fingerprint increased across ACLF grades, and was similar in patients with kidney failure and in those without, indicating that the fingerprint reflected not only decreased kidney excretion but also altered cell metabolism. The higher the ACLF-associated fingerprint intensity, the higher the plasma levels of inflammatory markers, tumor necrosis factor α, soluble CD206, and soluble CD163. ACLF was characterized by intense proteolysis and lipolysis; amino acid catabolism; extra-mitochondrial glucose metabolism through glycolysis, pentose phosphate, and D-glucuronate pathways; depressed mitochondrial ATP-producing fatty acid ß-oxidation; and extra-mitochondrial amino acid metabolism giving rise to metabotoxins. CONCLUSIONS: In ACLF, intense systemic inflammation is associated with blood metabolite accumulation and profound alterations in major metabolic pathways, in particular inhibition of mitochondrial energy production, which may contribute to the development of organ failures. LAY SUMMARY: Acute-on-chronic liver failure (ACLF), which develops in patients with cirrhosis, is characterized by intense systemic inflammation and organ failure(s). Because systemic inflammation is energetically expensive, its metabolic costs may result in organ dysfunction/failure. We identified a 38-metabolite blood fingerprint specific for ACLF that revealed mitochondrial dysfunction in peripheral organs. This may contribute to organ failures.

ESPEN guideline on clinical nutrition in liver disease.

This update of evidence-based guidelines (GL) aims to translate current evidence and expert opinion into recommendations for multidisciplinary teams responsible for the optimal nutritional and metabolic management of adult patients with liver disease. The GL was commissioned and financially supported by ESPEN. Members of the guideline group were selected by ESPEN. We searched for meta-analyses, systematic reviews and single clinical trials based on clinical questions according to the PICO format. The evidence was evaluated and used to develop clinical recommendations implementing the SIGN method. A total of 85 recommendations were made for the nutritional and metabolic management of patients with acute liver failure, severe alcoholic steatohepatitis, non-alcoholic fatty liver disease, liver cirrhosis, liver surgery and transplantation as well as nutrition associated liver injury distinct from fatty liver disease. The recommendations are preceded by statements covering current knowledge of the underlying pathophysiology and pathobiochemistry as well as pertinent methods for the assessment of nutritional status and body composition.

Clinical management of acute liver failure: Results of an international multi-center survey.

AIM: To assess the practice of caring for acute liver failure (ALF) patients in varying geographic locations and medical centers. METHODS: Members of the European Acute Liver Failure Consortium completed an 88-item questionnaire detailing management of ALF. Responses from 22 transplantation centers in 11 countries were analyzed, treating between 300 and 500 ALF cases and performing over 100 liver transplants (LT) for ALF annually. The questions pertained to details of the institution and their clinical activity, standards of care, referral and admission, ward- based care versus intensive care unit (ICU) as well as questions regarding liver transplantation - including criteria, limitations, and perceived performance. Clinical data was also collected from 13 centres over a 3 mo period. RESULTS: The interval between referral and admission of ALF patients to specialized units was usually less than 24 h and once admitted, treatment was provided by a multidisciplinary team. Principles of care of patients with ALF were similar among centers, particularly in relation to recognition of severity and care of the more critically ill. Centers exhibited similarities in thresholds for ICU admission and management of severe hepatic encephalopathy. Over 80% of centers administered n-acetyl-cysteine to ICU patients for non-paracetamol-related ALF. There was significant divergence in the use of prophylactic antibiotics and anti-fungals, lactulose, nutritional support and imaging investigations in admitted patients and in the monitoring and treatment of intra-cranial pressure (ICP). ICP monitoring was employed in 12 centers, with the most common indications being papilledema and renal failure. Most patients listed for transplantation underwent surgery within an average waiting time of 1-2 d. Over a period of 3 mo clinical data from 85 ALF patients was collected. Overall patient survival at 90-d was 76%. Thirty six percent of patients underwent emergency LT, with a 90% post transplant survival to hospital discharge, 42% survived with medical management alone. CONCLUSION: Alongside similarities in principles of care of ALF patients, major areas of divergence were present in key areas of diagnosis, monitoring, treatment and decision to transplant.

Multivariate metabotyping of plasma predicts survival in patients with decompensated cirrhosis.

BACKGROUND & AIMS: Predicting survival in decompensated cirrhosis (DC) is important in decision making for liver transplantation and resource allocation. We investigated whether high-resolution metabolic profiling can determine a metabolic phenotype associated with 90-day survival. METHODS: Two hundred and forty-eight subjects underwent plasma metabotyping by (1)H nuclear magnetic resonance (NMR) spectroscopy and reversed-phase ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry (UPLC-TOF-MS; DC: 80-derivation set, 101-validation; stable cirrhosis (CLD) 20 and 47 healthy controls (HC)). RESULTS: (1)H NMR metabotyping accurately discriminated between surviving and non-surviving patients with DC. The NMR plasma profiles of non-survivors were attributed to reduced phosphatidylcholines and lipid resonances, with increased lactate, tyrosine, methionine and phenylalanine signal intensities. This was confirmed on external validation (area under the receiver operating curve [AUROC]=0.96 (95% CI 0.90-1.00, sensitivity 98%, specificity 89%). UPLC-TOF-MS confirmed that lysophosphatidylcholines and phosphatidylcholines [LPC/PC] were downregulated in non-survivors (UPLC-TOF-MS profiles AUROC of 0.94 (95% CI 0.89-0.98, sensitivity 100%, specificity 85% [positive ion detection])). LPC concentrations negatively correlated with circulating markers of cell death (M30 and M65) levels in DC. Histological examination of liver tissue from DC patients confirmed increased hepatocyte cell death compared to controls. Cross liver sampling at time of liver transplantation demonstrated that hepatic endothelial beds are a source of increased circulating total cytokeratin-18 in DC. CONCLUSION: Plasma metabotyping accurately predicts mortality in DC. LPC and amino acid dysregulation is associated with increased mortality and severity of disease reflecting hepatocyte cell death.

Acute liver failure.

Acute liver failure (ALF) is a rare critical illness with high mortality whose successful management requires early recognition and effective initial management. Though it may result from a wide variety of causes, in the UK and much of the developed world most cases result from paracetamol-induced hepatotoxicity, and administration of antidotal N-acetyl cysteine at first recognition is key. Involvement of local critical care services should occur at an early stage for stabilisation, monitoring and supportive care with parallel discussion with specialist liver centres to identify those patients who may benefit from transfer. Prognostic criteria are applied to identify patients for emergency liver transplantation, and candidates for surgery are prioritised on waitlisting schemes. Outcomes now approach that of elective surgery. However, the majority of cases, and particularly those with paracetamol-induced disease, recover with supportive medical care alone. Overall outcomes for patients with ALF have improved dramatically over the last three decades, but mortality remains unacceptable and further advances in care are required.

Acute-on-chronic liver failure.

Acute-on-chronic liver failure combines an acute deterioration in liver function in an individual with pre-existing chronic liver disease and hepatic and extrahepatic organ failures, and is associated with substantial short-term mortality. Common precipitants include bacterial and viral infections, alcoholic hepatitis, and surgery, but in more than 40% of patients, no precipitating event is identified. Systemic inflammation and susceptibility to infection are characteristic pathophysiological features. A new diagnostic score, the Chronic Liver Failure Consortium (CLIF-C) organ failure score, has been developed for classification and prognostic assessment of patients with acute-on-chronic liver failure. Disease can be reversed in many patients, and thus clinical management focuses upon the identification and treatment of the precipitant while providing multiorgan-supportive care that addresses the complex pattern of physiological disturbance in critically ill patients with liver disease. Liver transplantation is a highly effective intervention in some specific cases, but recipient identification, organ availability, timing of transplantation, and high resource use are barriers to more widespread application. Recognition of acute-on-chronic liver failure as a clinically and pathophysiologically distinct syndrome with defined diagnostic and prognostic criteria will help to encourage the development of new management pathways and interventions to address the unacceptably high mortality.

'It doesn't do the care for you': a qualitative study of health care professionals' perceptions of the benefits and harms of integrated care pathways for end of life care.

OBJECTIVES: To understand healthcare professionals' perceptions of the benefits and potential harms of integrated care pathways for end-of-life care, to inform the development of future interventions that aim to improve care of the dying. DESIGN: Qualitative interview study with maximum variation sampling and thematic analysis. PARTICIPANTS: 25 healthcare professionals, including doctors, nurses and allied health professionals, interviewed in 2009. SETTING: A 950-bed South London teaching hospital. RESULTS: 4 main themes emerged, each including 2 subthemes. Participants were divided between (1) those who described mainly the benefits of integrated care pathways, and (2) those who talked about potential harms. Benefits focused on processes of care, for example, clearer, consistent and comprehensive actions. The recipients of these benefits were staff members themselves, particularly juniors. For others, this perceived clarity was interpreted as of potential harm to patients, where over-reliance on paperwork lead to prescriptive, less thoughtful care, and an absolution from decision-making. Independent of their effects on patient care, integrated care pathways for dying had (3) a symbolic value: they legitimised death as a potential outcome and were used as a signal that the focus of care had changed. However, (4) a weak infrastructure, including scanty education and training in end-of-life care and a poor evidence base, that appeared to undermine the foundations on which the Liverpool Care Pathway was built. CONCLUSIONS: The potential harms of integrated care pathways for the dying identified in this study were reminiscent of criticisms subsequently published by the Neuberger review. These data highlight: (1) the importance of collecting, reporting and using qualitative data when developing and evaluating complex interventions; (2) that comprehensive education and training in palliative care is critical for the success of any new intervention; (3) the need for future interventions to be grounded in patient-centred outcomes, not just processes of care.

Patients with acute-on-chronic liver failure have increased numbers of regulatory immune cells expressing the receptor tyrosine kinase MERTK.

BACKGROUND & AIMS: Characteristics of decompensated cirrhosis and acute-on-chronic liver failure (ACLF) include susceptibility to infection, immuneparesis, and monocyte dysfunction. MER receptor tyrosine kinase (MERTK) is expressed by monocytes and macrophages and contributes to down-regulation of innate immune responses. We investigated whether MERTK expression is altered on monocytes from patients with liver failure. METHODS: We analyzed blood and liver samples collected from patients admitted to the liver intensive therapy unit at King's College Hospital in London from December 2012 through July 2014. Patients had either ACLF (n = 41), acute decompensation of cirrhosis without ACLF (n = 9), cirrhosis without decompensation (n = 17), or acute liver failure (n = 23). We also analyzed samples from healthy individuals (controls, n = 29). We used flow cytometry to determine the level of innate immune function, and associated the findings with disease severity. We developed an assay to measure recruitment and migration of immune cells from the tissue parenchyma. Immunohistochemistry and confocal microscopy were used to determine levels of MERTK in bone marrow, liver, and lymph node tissues. We performed immunophenotype analyses and measured the production of tumor necrosis factor and interleukin 6 and intracellular killing of Escherichia coli by monocytes and peritoneal macrophages incubated with lipopolysaccharide, with or without an inhibitor of MERTK (UNC569). RESULTS: The number of monocytes and macrophages that expressed MERTK was greatly increased in the circulation, livers, and lymph nodes of patients with ACLF, compared with patients with stable cirrhosis and controls. MERTK expression (mean fluorescence intensity) correlated with the severity of hepatic and extrahepatic disease and systemic inflammatory responses. Based on immunophenotype, migration, and functional analyses, MERTK-expressing monocytes migrate across the endothelia to localize into tissue sites and regional lymph nodes. Expression of MERTK reduced the response of cultured monocytes to lipopolysaccharide; the addition of UNC569 restored production of inflammatory cytokines in response to lipopolysaccharide. CONCLUSIONS: Patients with ACLF have increased numbers of immunoregulatory monocytes and macrophages that express MERTK and suppress the innate immune response to microbes. The number of these cells correlates with disease severity and the inflammatory response. MERTK inhibitors restore production of inflammatory cytokines by immune cells from patients with ACLF, and might be developed to increase the innate immune response in these patients.