Multimodal decoding of human liver regeneration.

The liver has a unique ability to regenerate1,2; however, in the setting of acute liver failure (ALF), this regenerative capacity is often overwhelmed, leaving emergency liver transplantation as the only curative option3-5. Here, to advance understanding of human liver regeneration, we use paired single-nucleus RNA sequencing combined with spatial profiling of healthy and ALF explant human livers to generate a single-cell, pan-lineage atlas of human liver regeneration. We uncover a novel ANXA2+ migratory hepatocyte subpopulation, which emerges during human liver regeneration, and a corollary subpopulation in a mouse model of acetaminophen (APAP)-induced liver regeneration. Interrogation of necrotic wound closure and hepatocyte proliferation across multiple timepoints following APAP-induced liver injury in mice demonstrates that wound closure precedes hepatocyte proliferation. Four-dimensional intravital imaging of APAP-induced mouse liver injury identifies motile hepatocytes at the edge of the necrotic area, enabling collective migration of the hepatocyte sheet to effect wound closure. Depletion of hepatocyte ANXA2 reduces hepatocyte growth factor-induced human and mouse hepatocyte migration in vitro, and abrogates necrotic wound closure following APAP-induced mouse liver injury. Together, our work dissects unanticipated aspects of liver regeneration, demonstrating an uncoupling of wound closure and hepatocyte proliferation and uncovering a novel migratory hepatocyte subpopulation that mediates wound closure following liver injury. Therapies designed to promote rapid reconstitution of normal hepatic microarchitecture and reparation of the gut-liver barrier may advance new areas of therapeutic discovery in regenerative medicine.

Peritoneal flap hernioplasty for repair of incisional hernias after orthotopic liver transplantation.

BACKGROUND: Repair of incisional hernias following orthotopic liver transplantation (OLT) is a surgical challenge due to concurrent midline and transverse abdominal wall defects in the context of lifelong immunosuppression. The peritoneal flap hernioplasty addresses this problem by using flaps of the hernial sac to bridge the fascial gap and isolate the mesh from both the intraperitoneal contents and the subcutaneous space, exploiting the retro-rectus space medially and the avascular plane between the internal and external oblique muscles laterally. We report our short and long-term results of 26 consecutive liver transplant cases with incisional hernias undergoing repair with the peritoneal flap technique. METHODS: Post-OLT patients undergoing elective peritoneal flap hernioplasty for incisional hernias from Jan 1, 2010-Nov 1, 2017 were identified from the Lothian Surgical Audit system (LSA), a prospectively-maintained computer database of all surgical procedures in the Edinburgh region of south-east Scotland. Patient demographics and clinical data were obtained from the hospital case-notes. Follow-up data were obtained in Feb 2020. RESULTS: A total of 517 liver transplantations were performed during the inclusion period. Twenty-six of these (18 males, 69%) developed an incisional hernia and underwent a peritoneal flap repair. Median mesh size (Optilene Elastic, 48 g/m2, BBraun) was 900 cm2 (range 225-1500 cm2). The median time to repair following OLT was 33 months (range 12-70 months). Median follow-up was 54 months (range 24-115 months) and median postoperative stay was 5 days (range 3-11 days). Altogether, three patients (12%) presented with postoperative complications: 1 with hematoma (4%) and two with chronic pain (8%). No episodes of infection or symptomatic seroma were recorded. No recurrence was recorded within the follow-up period. CONCLUSION: Repair of incisional hernias in patients following liver transplantation with the Peritoneal Flap Hernioplasty is a safe procedure associated with few complications and a very low recurrence rate. We propose this technique for the reconstruction of incisional hernias following liver transplantation.

A pilot study evaluating GSK1070806 inhibition of interleukin-18 in renal transplant delayed graft function.

INTRODUCTION: Delayed graft function (DGF) following renal transplantation is a manifestation of acute kidney injury (AKI) leading to poor long-term outcome. Current treatments have limited effectiveness in preventing DGF. Interleukin-18 (IL18), a biomarker of AKI, induces interferon-γ expression and immune activation. GSK1070806, an anti-IL18 monoclonal antibody, neutralizes activated (mature) IL18 released from damaged cells following inflammasome activation. This phase IIa, single-arm trial assessed the effect of a single dose of GSK1070806 on DGF occurrence post donation after circulatory death (DCD) kidney transplantation. METHODS: The 3 mg/kg intravenous dose was selected based on prior studies and physiologically based pharmacokinetic (PBPK) modeling, indicating the high likelihood of a rapid and high level of IL18 target engagement when administered prior to kidney allograft reperfusion. Utilization of a Bayesian sequential design with a background standard-of-care DGF rate of 50% based on literature, and confirmed via extensive registry data analyses, enabled a statistical efficacy assessment with a minimal sample size. The primary endpoint was DGF frequency, defined as dialysis requirement ≤7 days post transplantation (except for hyperkalemia). Secondary endpoints included safety, pharmacokinetics and pharmacodynamic biomarkers. RESULTS: GSK1070806 administration was associated with IL18-GSK1070806 complex detection and increased total serum IL18 levels due to IL18 half-life prolongation induced by GSK1070806 binding. Interferon-γ-induced chemokine levels declined or remained unchanged in most patients. Although the study was concluded prior to the Bayesian-defined stopping point, 4/7 enrolled patients (57%) had DGF, exceeding the 50% standard-of-care rate, and an additional two patients, although not reaching the protocol-defined DGF definition, demonstrated poor graft function. Six of seven patients experienced serious adverse events (SAEs), including two treatment-related SAEs. CONCLUSION: Overall, using a Bayesian design and extensive PBPK dose modeling with only a small sample size, it was deemed unlikely that GSK1070806 would be efficacious in preventing DGF in the enrolled DCD transplant population. TRIAL REGISTRATION: NCT02723786.

Survey of the attitudes of hepatopancreatobiliary surgeons in northern Europe to resection of choledochal cysts in asymptomatic Western adults.

Background: Todani type 1 and 4 choledochal cysts are associated with a risk of developing cholangiocarcinoma. Resection is usually recommended, but data for asymptomatic Western adults are sparse. The aim of this study was to investigate diagnostic interpretation and attitudes towards resection of bile ducts for choledochal cysts in this subgroup of patients across northern European centres. Methods: Thirty hepatopancreatobiliary centres were provided with magnetic resonance cholangiopancreatograms and asked to discuss the management of six cases: asymptomatic non-Asian women, aged 30 or 60 years, with variable common bile duct (CBD) dilatations and different risk factors in the setting of a multidisciplinary team (MDT). The Fleiss κ value was calculated to estimate overall inter-rater agreement. Results: For all case scenarios combined, 83·3 and 86·7 per cent recommended resection for a CBD of 20 and 26 mm respectively, compared with 19·4 per cent for a CBD of 13 mm (P < 0·001). For patients aged 30 and 60 years, resection was recommended in 68·5 and 57·8 per cent respectively (P = 0·010). There was a trend towards recommending resection in the presence of a common channel, most pronounced in the 60-year-old patient. High amylase levels in the CBD aspirate led to recommendations to resect, but only for the 13-mm CBD dilatation. There were no differences related to centre size or region. MDT discussion was associated with recommendations to resect. Inter-rater agreement was 73·3 per cent (κ = 0·43, 95 per cent c.i. 0·38 to 0·48). Conclusion: The inter-rater agreement to resect was intermediate, and the recommendation was dependent mainly on the diameter of the CBD dilatation.

Antecedentes: Los quistes de colédoco (choledochal cysts, CC) tipo 1 y tipo 4 de Todani se asocian con un riesgo de desarrollar colangiocarcinoma. Generalmente se recomienda la resección de los mismos, pero los datos para pacientes adultos occidentales son escasos. El objetivo del presente estudio fue investigar la interpretación diagnóstica y actitudes respecto a la resección de las vías biliares por CC en este subgrupo de pacientes atendidos en centros del norte de Europa. Métodos: Se proporcionaron imágenes de colangiopancreatografía por resonancia magnética (magnetic resonance cholangiopancreatography, MRCP) a un total de 30 centros especializados en patología hepatobiliar y se les solicitó que discutieran el tratamiento de seis casos: pacientes del sexo femenino no asiáticas asintomáticas, de edad entre 30 y 60 años con dilataciones variables del colédoco (common bile duct, CBD) y con diferentes factores de riesgo en el marco de un equipo multidisciplinario (multidisciplinary team, MDT). Se calculó el índice kappa de Fleiss para estimar el acuerdo global entre los evaluadores. Resultados: Para todos los escenarios de casos combinados, un 83,3% y un 86,7% recomendaron la resección para un CBD de 20 y 26 mm, respectivamente, en comparación con un 19,4% para un CBD de 13 mm (P < 0,001). En el caso de un paciente de 30 y de 60 años, la resección se recomendó en el 68,5% y 57,8%, respectivamente (P = 0,010). Se observaron tendencias hacia recomendar la resección en presencia de un canal pancreático­biliar común, más pronunciado en el paciente de 60 años. Los niveles elevados de amilasa en el aspirado del CBD condujeron a la recomendación de resecar, pero solo en la dilatación del CBD de 13 mm. No hubo diferencias relacionadas con el tamaño del centro o la región. La discusión en el MDT se asoció con recomendaciones para la resección. El acuerdo entre evaluadores fue 73,3% con un índice kappa de 0,43 (i.c. del 95% 0,38­0,48). Conclusión: El acuerdo entre evaluadores para indicar la resección fue intermedio y la recomendación dependió principalmente del diámetro de la dilatación del CBD.

Resolving the fibrotic niche of human liver cirrhosis at single-cell level.

Liver cirrhosis is a major cause of death worldwide and is characterized by extensive fibrosis. There are currently no effective antifibrotic therapies available. To obtain a better understanding of the cellular and molecular mechanisms involved in disease pathogenesis and enable the discovery of therapeutic targets, here we profile the transcriptomes of more than 100,000 single human cells, yielding molecular definitions for non-parenchymal cell types that are found in healthy and cirrhotic human liver. We identify a scar-associated TREM2+CD9+ subpopulation of macrophages, which expands in liver fibrosis, differentiates from circulating monocytes and is pro-fibrogenic. We also define ACKR1+ and PLVAP+ endothelial cells that expand in cirrhosis, are topographically restricted to the fibrotic niche and enhance the transmigration of leucocytes. Multi-lineage modelling of ligand and receptor interactions between the scar-associated macrophages, endothelial cells and PDGFRα+ collagen-producing mesenchymal cells reveals intra-scar activity of several pro-fibrogenic pathways including TNFRSF12A, PDGFR and NOTCH signalling. Our work dissects unanticipated aspects of the cellular and molecular basis of human organ fibrosis at a single-cell level, and provides a conceptual framework for the discovery of rational therapeutic targets in liver cirrhosis.

Multicentre study of multidisciplinary team assessment of pancreatic cancer resectability and treatment allocation.

BACKGROUND: Multidisciplinary team (MDT) meetings have been adopted widely to ensure optimal treatment for patients with cancer. Agreements in tumour staging, resectability assessments and treatment allocation between different MDTs were assessed. METHODS: Of all patients referred to one hospital, 19 patients considered to have non-metastatic pancreatic cancer for evaluation were selected randomly for a multicentre study of MDT decisions in seven units across Northern Europe. Anonymized clinical information and radiological images were disseminated to the MDTs. All patients were reviewed by the MDTs for radiological T, N and M category, resectability assessment and treatment allocation. Each MDT was blinded to the decisions of other teams. Agreements were expressed as raw percentages and Krippendorff's α values, both with 95 per cent confidence intervals. RESULTS: A total of 132 evaluations in 19 patients were carried out by the seven MDTs (1 evaluation was excluded owing to technical problems). The level of agreement for T, N and M categories ranged from moderate to near perfect (46·8, 61·1 and 82·8 per cent respectively), but there was substantial variation in assessment of resectability; seven patients were considered to be resectable by one MDT but unresectable by another. The MDTs all agreed on either a curative or palliative strategy in less than half of the patients (9 of 19). Only fair agreement in treatment allocation was observed (Krippendorff's α 0·31, 95 per cent c.i. 0·16 to 0·45). There was a high level of agreement in treatment allocation where resectability assessments were concordant. CONCLUSION: Considerable disparities in MDT evaluations of patients with pancreatic cancer exist, including substantial variation in resectability assessments.

Systematic review of management of incidental gallbladder cancer after cholecystectomy.

BACKGROUND: Gallbladder cancer is rare, but cancers detected incidentally after cholecystectomy are increasing. The aim of this study was to review the available data for current best practice for optimal management of incidental gallbladder cancer. METHODS: A systematic PubMed search of the English literature to May 2018 was conducted. RESULTS: The search identified 12 systematic reviews and meta-analyses, in addition to several consensus reports, multi-institutional series and national audits. Some 0·25-0·89 per cent of all cholecystectomy specimens had incidental gallbladder cancer on pathological examination. Most patients were staged with pT2 (about half) or pT1 (about one-third) cancers. Patients with cancers confined to the mucosa (T1a or less) had 5-year survival rates of up to 100 per cent after cholecystectomy alone. For cancers invading the muscle layer of the gallbladder wall (T1b or above), reresection is recommended. The type, extent and timing of reresection remain controversial. Observation time may be used for new cross-sectional imaging with CT and MRI. Perforation at initial surgery had a higher risk of disease dissemination. Gallbladder cancers are PET-avid, and PET may detect residual disease and thus prevent unnecessary surgery. Routine laparoscopic staging before reresection is not warranted for all stages. Risk of peritoneal carcinomatosis increases with each T category. The incidence of port-site metastases is about 10 per cent. Routine resection of port sites has no effect on survival. Adjuvant chemotherapy is poorly documented and probably underused. CONCLUSION: Management of incidental gallbladder cancer continues to evolve, with more refined suggestions for subgroups at risk and a selective approach to reresection.

Patient experience and overall satisfaction after emergency abdominal surgery.

BACKGROUND: There is a growing recognition of the importance of patient experience in healthcare, however little is known in the context of emergency abdominal surgery. This study sought to quantify the association between patient experience and overall satisfaction. METHODS: Patient demographics, operation details and 30-day clinical outcome data of consecutive patients undergoing emergency abdominal surgery were collected. Data was collected using validated Patient Reported Experience Measures (PREMs) questionnaires. Categorical data were tested using Mann Whitney U test. Multivariable regression was used to determine independent factors associated with satisfaction. RESULTS: In a well-fitting multivariable analysis (R2 = 0.71), variables significantly associated with a higher global satisfaction score were "sufficient information given about treatment" (ß = 0.86, 95% CI 0.01-1.70, p = 0.047), "sufficient explanation of risks and benefits of surgery" (ß = 1.26, 95% CI 0.18-2.34, p = 0.020), "absence of night-time noise" (ß = 1.35, 95% CI 0.56-2.14, p = 0.001) and "confidence and trust in nurses" (ß = 1.51, 95% CI 0.54-2.49, p = 0.003). CONCLUSIONS: Overall patient satisfaction was strongly associated with perceptions of good communication and transfer of information. Confidence and trust in the clinical team is an important determinant of patient experience. Improving the ward environment by reducing noise at night may also improve the overall experience and satisfaction in emergency surgery.

The Influence of Clinical and Patient-Reported Outcomes on Post-surgery Satisfaction in Cholecystectomy Patients.

BACKGROUND: Patient-reported outcomes (PROMs) and post-operative satisfaction have become a growing focus of surgical outcome evaluation and are considered key components of the movement towards patient-centred care. The aim was to compare the association of traditional clinical outcome measures and PROMs with post-surgery satisfaction in cholecystectomy patients. METHODS: Patients who had undergone elective or emergency cholecystectomy for gallstone disease were sent validated PROM questionnaires, and telephone follow-up was performed in all cases. Categorical data were compared with the Chi-square and Fisher's exact tests. Satisfaction was investigated using a "top-box" approach, and multivariable logistic regression was performed for factors significantly (p < 0.05) associated with satisfaction in univariable analyses. RESULTS: A total of 234 patients underwent cholecystectomy between 1 March 2014 and 1 May 2014, and 147 patients (63%) completed the questionnaire. 104/147 (71%) reported being "very satisfied" with their surgical outcome. In univariable analyses, satisfaction showed significant association with an absence of hospital-recorded 30-day complications (OR = 4.11, 95% CI 1.29-13.84), but not re-attendance, readmission, or length of stay. In a multiple regression analysis, no traditional clinical outcome measures were associated with satisfaction. By contrast, self-perceived health (OR = 4.04, 95% CI 1.44-11.86), the absence of patient-reported wound pain (OR = 6.11, 95% CI 1.83-21.74), and a return to normal leisure activities (OR = 11.14, 95% CI 2.61-55.26) were associated with satisfaction. CONCLUSION: PROMs are the major determinants of patient satisfaction following cholecystectomy. When assessing outcomes following cholecystectomy, the measurement of clinical outcomes alone is inadequate and should be supplemented by the use of PROMs.

Randomized clinical trial of perioperative nerve block and continuous local anaesthetic infiltration via wound catheter versus epidural analgesia in open liver resection (LIVER 2 trial).

BACKGROUND: Analgesia after liver surgery remains controversial. A previous randomized trial of continuous wound infiltration (CWI) versus thoracic epidural analgesia (TEA) after liver surgery (LIVER trial) showed a faster recovery time in the wound infiltration group but better early postoperative pain scores in the TEA group. High-level evidence is, however, limited and opinion remains divided. The aim was to determine whether there is a difference in functional recovery time between patients having CWI plus abdominal nerve blocks versus TEA after liver resection. METHODS: A randomized unblinded clinical trial of patients undergoing open liver resection was commenced in December 2012, with follow-up to August 2014. Patients were randomized to receive either wound catheter and nerve block (CWI group) or TEA for 48 h after surgery. The primary outcome measure was functional recovery time. Secondary outcomes were pain scores, complication rates, inflammatory response and central venous pressure (CVP) during transection. RESULTS: Of 50 patients randomized initially to each group, 44 received TEA and 49 CWI. Median (i.q.r.) recovery time was 6·5 (5-9·75) and 5·75 (4-7) days in the TEA and CWI groups respectively (P = 0·036). Pain scores were not significantly different between the two groups, and there were no differences in morbidity, inflammatory response or CVP during transection. CONCLUSION: Wound infiltration is associated with a reduced time to recovery after open liver resection compared with epidural analgesia. TEA does not offer an advantage over CWI in terms of attenuation of the inflammatory response or pain scores. REGISTRATION NUMBER: NCT01747122 ( http://www.clinicaltrials.gov).

Meta-analysis of ischaemic preconditioning for liver resections.

BACKGROUND: Vascular clamping reduces blood loss during liver resection but leads to ischaemia-reperfusion injury. Ischaemic preconditioning (IP) may reduce this. This study aimed to evaluate IP in liver resection under clamping. METHODS: This was a systematic review and meta-analysis of randomized clinical trials (RCTs) evaluating IP in adults undergoing liver resection under either continuous clamping (CC) or intermittent clamping (IC). Primary outcomes were mortality, liver failure and morbidity. Secondary outcomes included duration of operation, blood loss, length of hospital stay, length of intensive therapy unit stay, transfusion requirements, prothrombin time, and bilirubin and aminotransferase levels. Weighted mean differences were calculated for continuous data, and pooled odds ratios (ORs) for dichotomous data. Results were produced with a random-effects model with 95 per cent confidence intervals (c.i.). RESULTS: A total of 2960 records were identified and 11 RCTs included 669 patients (IP 331, control 338). No significant difference in mortality (6 RCTs; IP 186, control 190; OR 1·36, 95 per cent c.i. 0·13 to 13·68; P = 0·80) or morbidity (6 RCTs; IP 186, control 190; OR 0·58, 0·31 to 1·07; P = 0·08) was found for IP plus CC versus CC. Nor was there a significant difference in mortality (4 RCTs; IP 122, control 121; OR 1·33, 0·24 to 7·32; P = 0·74) or morbidity (4 RCTs; IP 122, control 121; OR 0·87, 0·52 to 1·47; P = 0·61) for IP plus (CC or IC) versus IC. No significant differences were found for secondary outcome measures. CONCLUSION: This meta-analysis failed to find a significant benefit of IP in liver resection.

Systematic review and meta-analysis of continuous local anaesthetic wound infiltration versus epidural analgesia for postoperative pain following abdominal surgery.

BACKGROUND: Local anaesthetic wound infiltration techniques reduce opiate requirements and pain scores. Wound catheters have been introduced to increase the duration of action of local anaesthetic by continuous infusion. The aim was to compare these infiltration techniques with the current standard of epidural analgesia. METHODS: A meta-analysis of randomized clinical trials (RCTs) evaluating wound infiltration versus epidural analgesia in abdominal surgery was performed. The primary outcome was pain score at rest after 24 h on a numerical rating scale. Secondary outcomes were pain scores at rest at 48 h, and on movement at 24 and 48 h, with subgroup analysis according to incision type and administration regimen(continuous versus bolus), opiate requirements, nausea and vomiting, urinary retention, catheter-related complications and treatment failure. RESULTS: Nine RCTs with a total of 505 patients were included. No differences in pain scores at rest 24 h after surgery were detected between epidural and wound infiltration. There were no significant differences in pain score at rest after 48 h, or on movement at 24 or 48 h after surgery. Epidural analgesia demonstrated a non-significant a trend towards reduced pain scores on movement and reduced opiate requirements. There was a reduced incidence of urinary retention in the wound catheter group. CONCLUSION: Within a heterogeneous group of RCTs, use of local anaesthetic wound infiltration was associated with pain scores comparable to those obtained with epidural analgesia. Further procedure-specific RCTs including broader measures of recovery are recommended to compare the overall efficacy of epidural and wound infiltration analgesic techniques.

Outcomes following a dedicated period of research during surgical training.

With recent 'working-time'-related changes to surgical training structure, the value of dedicated research during surgical training has been questioned. Online survey examining career and academic outcomes following a period of surgically related dedicated research at a Scottish University between 1972 and 2007. Of 58 individuals identified, contact details were available for 49 and 43 (88%) responded. Ninety-five percent (n = 41) of respondents continue to pursue a career in surgery and 41% (n = 17) are currently in academic positions. Ninety-one percent (n = 39) had published one or more first-author peer-reviewed articles directly related to their research, with 53% (n = 23) publishing three or more. Respondents with a clinical component to their research published significantly more papers than those with purely laboratory-based research (P = 0.04). Eighty-one percent (n = 35) thought that research was necessary for career progression, but only 42% (n = 18) felt research should be integral to training. In conclusion, the majority of surgical trainees completing a dedicated research period, published papers and continued to pursue a surgical career with a research interest. A period of dedicated research was thought necessary for career progression, but few thought dedicated research should be integral to surgical training.

The Scottish Liver Transplant Unit: current and future perspectives.

The Scottish Liver Transplant Unit (SLTU) opened in 1992 and has now performed over 900 liver transplants. During this time there have been major changes in both organ donation and transplantation. Currently liver transplantation is restricted by limited organ supply. Scotland has one of the lowest rates of organ donation in Europe and one of the most rapidly increasing rates of cirrhosis. The consequent waiting list mortality has driven innovations including increasing use of marginal grafts, organs donated after cardiac death, split-liver transplants and the development of living-donor liver transplantation. To maintain liver transplantation, there is an urgent need to increase organ donation rates and to find novel treatments which optimize outcomes from marginal grafts. This review addresses the surgical aspects of liver transplantation and how these have evolved over the two past decades. Major changes are currently underway in organ donation organization, and there is continuing refinement of organ treatment and storage. A number of measures to maintain and improve organ preservation and function are currently being evaluated in clinical trials, and cell therapy holds significant potential for the future. Scotland has a rising need for liver transplantation and the SLTU continues to provide high-quality care and to be at the forefront of the latest advances in organ transplantation.

Systematic review and meta-analysis of survival following extracorporeal liver support.

BACKGROUND: Extracorporeal liver support (ELS) systems offer the potential to prolong survival in acute and acute-on-chronic liver failure. However, the literature has been unclear on their specific role and influence on mortality. This meta-analysis aimed to test the hypothesis that ELS improves survival in acute and acute-on-chronic liver failure. METHODS: Clinical trials citing MeSH terms 'liver failure' and 'liver, artificial' were identified by searching MEDLINE, Embase and the Cochrane registry of randomized controlled trials (RCTs) between January 1995 and January 2010. Only RCTs comparing ELS with standard medical therapy in acute or acute-on-chronic liver failure were included. A predefined data collection pro forma was used and study quality assessed according to Consolidated Standards of Reporting Trials (CONSORT) criteria. Risk ratio was used as the effect size measure according to a random-effects model. RESULTS: The search strategy revealed 74 clinical studies including 17 RCTs, five case-control studies and 52 cohort studies. Eight RCTs were suitable for inclusion, three addressing acute liver failure (198 participants) and five acute-on-chronic liver failure (157 participants). The mean CONSORT score was 14 (range 11-20). Overall ELS therapy significantly improved survival in acute liver failure (risk ratio 0·70; P = 0·05). The number needed to treat to prevent one death in acute liver failure was eight. No significant survival benefit was demonstrated in acute-on-chronic liver failure (risk ratio 0·87; P = 0·37). CONCLUSION: ELS systems appear to improve survival in acute liver failure. There is, however, no evidence that they improve survival in acute-on-chronic liver failure.