John O’Grady

Evolution of indications and results of liver transplantation in Europe. A report from the European Liver Transplant Registry (ELTR).

Royal Free Hospital, London, UKIntroductionBackground of the European Liver Transplant RegistrySince 1968 the European Liver Transplant Registry (ELTR) collectsprospectively the data of liver transplantation (LT) in 145 centersall over Europe. It represents more than 95% of the overallEuropean data compared to the published official figures [1]. Thiscollectionismadeprospectivelythroughastandardizedquestion-naire. The first part of the questionnaire includes items regardingdate andindicationfor LT,donor andrecipientdata, surgical tech-niqueofLT,andtheimmediatepostoperativeimmunosuppressiontherapy. The second part concerns graft and patient outcome, andimmunosuppressive regimen follow-up. Participation in the ELTRis voluntary and a standard computerized database is provided tocontributing centers with detailed instructions for the collectionof accurate and uniform information [2].Along with reports concerning LT for specific hepatic diseases[3–12],ELTRhasallowedthedevelopmentofriskmodelsforliver-transplantation mortality according to the characteristics of thedonor and recipient, and of the transplant procedure [13,14].Qualityofthedataisassessedroutinely.Aregularauditingpro-cessisconductedeachyeartoensurethereliabilityofthescientificanalysis of the data, a control of the good adequacy between ELTRquestionnaire and patient charts is performed by randomly con-ductedauditvisits.ResultsoftheseauditvisitshaveindicatedthatELTR data were reliable and the scientific results of ELTR can beconsidered credible and representative of LT in Europe [15–18].In addition, a control quality program has been developed inter-nally. The data are subjected to checks for completeness, consis-tency, and range. Comprehensive logical intra- and inter-updatesare performed. Moreover, the ELTR has established agreementswith the European Organ Sharing Organizations (OSO): UnitedKingdom Transplant Service Support Authority (UKTransplant),Spanish Organizacion Nacional de Transplantes (ONT), Scandina-vian Scanditransplant (SKT), Dutch Transplant Foundation (NTS),Eurotransplant (ET), French Agence de la Biomedecine (ABM) toexchangedatacollectedfromEuropeanCentersandtocrosscheckcommon data between OSO and ELTR.Patients and methodsWe have first considered all data since 1968 to show the evolu-tion of results of LT in Europe since its initial development. Therest of the analysis has been undertaken during two differentperiods: (a) from January 1988 to December 2009 (89,865 LT –80,347 patients), where the date from January 1988 was chosenJournal of Hepatology 2012 vol. 57

Prednisolone or Pentoxifylline for Alcoholic Hepatitis

BACKGROUND Alcoholic hepatitis is a clinical syndrome characterized by jaundice and liver impairment that occurs in patients with a history of heavy and prolonged alcohol use. The short-term mortality among patients with severe disease exceeds 30%. Prednisolone and pentoxifylline are both recommended for the treatment of severe alcoholic hepatitis, but uncertainty about their benefit persists. METHODS We conducted a multicenter, double-blind, randomized trial with a 2-by-2 factorial design to evaluate the effect of treatment with prednisolone or pentoxifylline. The primary end point was mortality at 28 days. Secondary end points included death or liver transplantation at 90 days and at 1 year. Patients with a clinical diagnosis of alcoholic hepatitis and severe disease were randomly assigned to one of four groups: a group that received a pentoxifylline-matched placebo and a prednisolone-matched placebo, a group that received prednisolone and a pentoxifylline-matched placebo, a group that received pentoxifylline and a prednisolone-matched placebo, or a group that received both prednisolone and pentoxifylline. RESULTS A total of 1103 patients underwent randomization, and data from 1053 were available for the primary end-point analysis. Mortality at 28 days was 17% (45 of 269 patients) in the placebo-placebo group, 14% (38 of 266 patients) in the prednisolone-placebo group, 19% (50 of 258 patients) in the pentoxifylline-placebo group, and 13% (35 of 260 patients) in the prednisolone-pentoxifylline group. The odds ratio for 28-day mortality with pentoxifylline was 1.07 (95% confidence interval [CI], 0.77 to 1.49; P=0.69), and that with prednisolone was 0.72 (95% CI, 0.52 to 1.01; P=0.06). At 90 days and at 1 year, there were no significant between-group differences. Serious infections occurred in 13% of the patients treated with prednisolone versus 7% of those who did not receive prednisolone (P=0.002). CONCLUSIONS Pentoxifylline did not improve survival in patients with alcoholic hepatitis. Prednisolone was associated with a reduction in 28-day mortality that did not reach significance and with no improvement in outcomes at 90 days or 1 year. (Funded by the National Institute for Health Research Health Technology Assessment program; STOPAH EudraCT number, 2009-013897-42 , and Current Controlled Trials number, ISRCTN88782125 ).

Lessons from look-back in acute liver failure? A single centre experience of 3300 patients.

BACKGROUND & AIMS Acute liver failure (ALF) is a rapidly progressive critical illness with high mortality. Complex intensive care unit (ICU) protocols and emergency liver transplantation (ELT) are now often available, but rarity and severity of illness have limited its study and evidence-base for care. We reviewed patients treated over a 35-year period at a specialist high-volume ICU, quantifying changes in disease aetiology, severity and evolution of ICU support and ELT use and outcome. METHODS Review of adult patients admitted during the period 1973-2008, with acute liver dysfunction and coagulopathy with overt hepatic encephalopathy (ALF) and those without (acute liver injury; ALI). RESULTS 3305 patients fulfilled inclusion criteria, 2095 with ALF. Overall hospital survival increased from 30% in 1973-78 to 76% in 2004-08; in ALF from 17% to 62% (both p<0.0001). In ALF patients treated without ELT, survival rose from 17% to 48% (p<0.0001); in those undergoing ELT (n=387) from 56% in 1984-88 to 86% in 2004-08 (p<0.01). Coincident with drug sales-restriction, paracetamol-related admissions fell significantly. Viral admissions fell from 56% to 17% of non-paracetamol cases (p<0.0001). Admission markers of liver injury severity fell significantly and the proportion of patients with intracranial hypertension (ICH) fell from 76% in 1984-88 to 20% in 2004-08 (p<0.0001). In those with ICH, mortality fell from 95% to 55% (p<0.0001). CONCLUSIONS The nature and outcome of ALF have transformed over 35 years, with major improvements in survival and a fall in prevalence of cerebral oedema and ICH, likely consequent upon earlier illness recognition, improved ICU care, and use of ELT.

Outcome after wait-listing for emergency liver transplantation in acute liver failure: A single centre experience

BACKGROUND/AIMS Though emergency liver transplantation (ELT) is an established treatment for severe acute liver failure (ALF), outcomes are inferior to elective surgery. Despite prioritization, many patients deteriorate, becoming unsuitable for ELT. METHODS We examined a single-centre experience of 310 adult patients with ALF registered for ELT over a 10-year period to determine factors associated with failure to transplant, and in those patients undergoing ELT, those associated with 90-day mortality. RESULTS One hundred and thirty-two (43%) patients had ALF resulting from paracetamol and 178 (57%) from non-paracetamol causes. Seventy-four patients (24%) did not undergo surgery; 92% of these died. Failure to transplant was more likely in patients requiring vasopressors at listing (hazard ratio 1.9 (95% CI 1.1-3.6)) paracetamol aetiology (2.5 (1.4-4.6)) but less likely in blood group A (0.5 (0.3-0.9)). Post-ELT survival at 90-days and one-year increased from 66% and 63% in 1994-1999 to 81% and 79% in 2000-2004 (p<0.01). Four variables were associated with post-ELT mortality; age >45 years (3 (1.7-5.3)), vasopressor requirement (2.2 (1.3-3.8), transplantation before 2000 (1.9 (1.1-3.3)) and use of high-risk grafts (2.3 (1.3-4.2). CONCLUSIONS The data indicate improved outcomes in the later era, despite higher level patient dependency and greater use of high-risk grafts, through improved graft/recipient matching.

Liver transplantation for acute liver failure in Europe: Outcomes over 20 years from the ELTR database

BACKGROUND & AIMS Liver transplantation for acute liver failure (ALF) still has a high early mortality. We evaluated changes during 20 years, and identified risk factors for poor outcome. METHODS Donor, graft, and recipient variables from the European Liver Transplant Registry database (January 1988-June 2009), were analysed. Aetiologies and time periods were compared. Three and 12-month survival models were generated from separate training data sets, which were validated. A sub-analysis was performed for recipient older than 50 years. RESULTS Four thousand nine hundred and three patients were evaluated. One, 5- and 10-year patient, and graft survival rates were 74%, 68%, 63%, and 63%, 57%, 50%, respectively. Survival was better in 2004-2009 compared to previous quinquennia (p<0.001), despite donors >60 years increased from 1.8% to 21%. A higher incidence of suicide or non-adherence occurred in paracetamol-related ALF (p<0.001). Death or graft loss were independently associated with male recipients (adjusted OR 1.25), recipient >50 years (1.26), incompatible ABO matching (1.93), donors >60 years (1.21), and reduced size graft (1.54). For both 3- and 12-month models, incompatible ABO matching, non-viral aetiology, reduced size graft, and non-UW preservation fluid were associated with increased mortality/graft loss, whereas male recipients and age >50 years were associated only at 12 months. Both models had reasonable discriminative ability with good calibration at 3 months. Recipients >50 years, combined with donors >60 years resulted in 57% mortality/graft loss within the first year. CONCLUSIONS Survival after liver transplantation has improved despite increases in donor/recipient age. Recipients >50 years paired with donors >60 years had a very high mortality/graft loss within the first year.

Sclerosing encapsulating peritonitis after orthotopic liver transplantation

BACKGROUND The etiology of abdominal cocoon (a rare cause of intestinal obstruction) is unknown. It has occurred in adolescent girls, cirrhotic patients after peritoneal-venous shunting, and patients undergoing peritoneal dialysis. We report our experience with patients after orthotopic liver transplantation (OLT). METHODS Five patients (4 male, 1 female, aged 16 to 57 years) underwent OLT (3 whole liver, 2 right lobe grafts) and subsequently developed abdominal cocoon. RESULTS All developed pyrexia by 66 +/- 21 hours posttransplant. Additional symptoms (epigastric discomfort and intermittent vomiting) occurred 12 +/- 10 days later. Bacterial peritonitis was confirmed by microbiology in 2 cases and diagnosed by exclusion in the others. C-reactive protein levels were persistently elevated in all patients (35 to 82 mg/L). While abdominal CT consistently demonstrated marked ascites with the small intestine confined to a particular area of the abdomen, intestinal contrast studies and ultrasound were not diagnostic. All patients underwent surgical removal of the cocoon membrane by 58 +/- 22 days after transplant. CONCLUSIONS Sclerosing peritonitis may complicate liver transplantation and occurs because of low-grade intra-abdominal sepsis.

Prognosis of acute severe autoimmune hepatitis (AS-AIH): The role of corticosteroids in modifying outcome

BACKGROUND & AIMS No standardised definition exists for acute, severe AIH (AS-AIH). However, rapid identification of AS-AIH and early corticosteroid therapy may prevent the need for liver transplantation (LT). We set out to determine the clinical outcomes of patients with AS-AIH presenting to our institution with particular focus on the role of corticosteroids. METHODS Retrospective analysis of a prospectively collated database identified patients presenting with AS-AIH from 1999 to 2009. We defined AS-AIH as an acute presentation with an INR of ⩾1.5 at any time without histological evidence of cirrhosis. RESULTS 32 patients were identified with AS-AIH. Among the 32 AS-AIH patients 23 were treated with corticosteroids of whom 10 (48%) required LT, whilst all 9 untreated patients required LT (p = 0.01). Untreated patients demonstrated higher MELD scores at presentation (34 vs. 28 p = 0.01) and a non-significant decrease in episodes of sepsis but no difference in sepsis or mortality was observed between untreated or treated patients (11% vs. 26% p = 0.6 and 22% vs. 17% p = 0.99 respectively). Among treated patients, no difference in MELD scores was observed between responders or failures. Despite 59% undergoing LT, six deaths (19%) occurred. CONCLUSION In a well characterised cohort of patients with AS-AIH, almost 60% required LT and 20% died. There was no difference in prognostic scores between steroid responders and failures and steroid exposure did not appear to jeopardise survival. Patients with AS-AIH should be considered for a trial of corticosteroids expediently whilst a thorough search for sepsis and assessment for LT should occur if clinical deterioration or encephalopathy develops.

Timing and benefit of liver transplantation in acute liver failure

The case for using emergency liver transplantation in acute liver failure was made two decades ago by a series of single centre experiences. The development of models identifying a poor prognosis assisted the selection of patients for liver transplantation but none of these delivers both high sensitivity and specificity for prediction of death. Enhanced sensitivity favours the individual patient while enhanced specificity targets the pool of organs available at those who will derive greatest benefit. The non-transplant survival rates have improved considerably for certain cohorts of patients and these prognostic models have not been adjusted to reflect these changes. The presumption of transplant benefit can no longer be taken as established in paracetamol-related acute liver failure and a policy review is appropriate. In other scenarios, such as seronegative hepatitis and the phenotype of sub-acute liver failure, spontaneous survival rates remain low and the basis for liver transplantation remains sound. Outcomes after liver transplantation are improving but are not yet comparable to elective transplantation. The understanding of factors associated with failure after liver transplantation is improving but accurate definition of futility has not yet been attained.

Steroids or pentoxifylline for alcoholic hepatitis (STOPAH): study protocol for a randomised controlled trial

AbstractBackgroundAlcoholic hepatitis is the most florid presentation of alcohol-related liver disease. In its severe form, defined by a Maddrey’s discriminant function (DF) ≥32, the 28-day mortality rate is approximately 35%. A number of potential treatments have been subjected to clinical trials, of which two, corticosteroids and pentoxifylline, may have therapeutic benefit. The role of corticosteroids is controversial as trial results have been inconsistent, whereas the role of pentoxifylline requires confirmation as only one previous placebo-controlled trial has been published.Methods/designSTOPAH is a multicentre, double-blind, factorial (2 × 2) trial in which patients are randomised to one of four groups: 1.Group A: placebo / placebo2.Group B: placebo / prednisolone3.Group C: pentoxifylline / placebo4.Group D: pentoxifylline / prednisolone The trial aims to randomise 1,200 patients with severe alcoholic hepatitis, in order to provide sufficient power to determine whether either of the two interventions is effective. The primary endpoint of the study is mortality at 28 days, with secondary endpoints being mortality at 90 days and 1 year.DiscussionSTOPAH aims to be a definitive study to resolve controversy around the existing treatments for alcoholic hepatitis. Eligibility criteria are based on clinical parameters rather than liver biopsy, which are aligned with standard clinical practice in most hospitals. The use of a factorial design will allow two treatments to be evaluated in parallel, with efficient use of patient numbers to achieve high statistical power.Trial registrationEudraCT reference number: 2009-013897-42ISRCTN reference number: ISRCTN88782125

The prevalence of the activating JAK2 tyrosine kinase mutation in chronic porto‐splenomesenteric venous thrombosis

Aliment Pharmacol Ther 31, 1330–1336