James Neuberger

Impact factors: uses and abuses

Quantitative assessment of the scientific merit of journals and articles is being used increasingly to assess and compare researchers and institutions. The most commonly used measure is the 2 year Impact Factor, which broadly reflects the number of times each article in the journal has been cited over the previous 2 years. There are clear limitations to the use of such measures – not least, Impact Factors reflect the journal not the article, vary with time and correlate only poorly with perceived excellence. Simple comparison of impact factors in different specialties may be misleading. Review journals often have higher Impact Factors than those with original data. Both authors and editors can try to manipulate journal Impact Factors. However, despite valid concerns, Impact Factors are widely used and offer, at present, the best simple tool for comparison of output. Like all measures, the use of Impact Factors has to be tempered with knowledge of their limitations and common sense used in interpreting any data based on any analysis.

Autoimmune liver disease, autoimmunity and liver transplantation.

Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) represent the three major autoimmune liver diseases (AILD). PBC, PSC, and AIH are all complex disorders in that they result from the effects of multiple genes in combination with as yet unidentified environmental factors. Recent genome-wide association studies have identified numerous risk loci for PBC and PSC that host genes involved in innate or acquired immune responses. These loci may provide a clue as to the immune-based pathogenesis of AILD. Moreover, many significant risk loci for PBC and PSC are also risk loci for other autoimmune disorders, such type I diabetes, multiple sclerosis and rheumatoid arthritis, suggesting a shared genetic basis and possibly similar molecular pathways for diverse autoimmune conditions. There is no curative treatment for all three disorders, and a significant number of patients eventually progress to end-stage liver disease requiring liver transplantation (LT). LT in this context has a favourable overall outcome with current patient and graft survival exceeding 80% at 5years. Indications are as for other chronic liver disease although recent data suggest that while lethargy improves after transplantation, the effect is modest and variable so lethargy alone is not an indication. In contrast, pruritus rapidly responds. Cholangiocarcinoma, except under rigorous selection criteria, excludes LT because of the high risk of recurrence. All three conditions may recur after transplantation and are associated with a greater risk of both acute cellular and chronic ductopenic rejection. It is possible that a crosstalk between alloimmune and autoimmune response perpetuate each other. An immunological response toward self- or allo-antigens is well recognised after LT in patients transplanted for non-autoimmune indications and sometimes termed de novo autoimmune hepatitis. Whether this is part of the spectrum of rejection or an autoimmune process is not clear. In this manuscript, we review novel findings about disease processes and mechanisms that lead to autoimmunity in the liver and their possible involvement in the immune response vs. the graft after LT.

Elective liver transplant list mortality: development of a United Kingdom end-stage liver disease score.

Background. Prediction of short-term survival probability is important in the selection and allocation of patients for liver transplantation, and the Mayo End-Stage Liver Disease (MELD) score has been used in these contexts. The aim of this study was to develop and validate a model for estimation of short-term prognosis of patients selected for elective liver transplantation in the United Kingdom. Methods. A modeling dataset was based on 1103 adult patients registered for a first elective liver transplant in the United Kingdom between April 1, 2003, and March 31, 2006, and a validation dataset based on 452 patients registered between April 1, 2006, and March 31, 2007. The final model (United Kingdom End-Stage Liver Disease) included international normalized ratio, serum creatinine, bilirubin, and sodium. Results. The model, based on the modeling dataset, accurately predicted mortality on the transplant list in the validation dataset and proved to be a better predictor than MELD or MELD-Na. The United Kingdom End-Stage Liver Disease score was not associated with overall posttransplant survival but was associated with both the duration of intensive care unit stay and overall initial hospital stay. Conclusion. This model, developed specifically for patients awaiting liver transplantation, provides a useful tool for the selection of patients for liver transplantation and the allocation of donor livers.

Guidelines for liver transplantation for patients with non-alcoholic steatohepatitis

Non-alcoholic steatohepatitis (NASH) is an increasing cause of liver disease necessitating liver transplantation. In patients with advanced NASH, there are often coexistent clinical issues that impact on the outcome of liver transplantation. There are no guidelines for the assessment and management of patients with NASH undergoing liver transplantation.nnA group was therefore invited by the Council of the British Transplant Society (BTS) to prepare guidelines for the management of NASH before and after liver transplantation. The guideline is approved by the British Society of Gastroenterology, the British Association for the Study of Liver and NHS Blood and Transplant.nnThe first draft was written by Dr P N Newsome (senior lecturer and consultant hepatologist, Liver Unit, University Hospital Birmingham NHS Foundation Trust) in Autumn 2010 with contributions from the following guideline group: Dr Peter Henriksen (consultant cardiologist and honorary senior lecturer, Edinburgh Heart Centre, NHS Lothian, University Hospitals Division), Professor C P Day (Professor of Liver Medicine, Institute of Cellular Medicine, Newcastle University), Dr D Thorburn (consultant hepatologist, Liver Unit, Royal Free Hospital, London), Mr D F Mirza (consultant hepatobiliary and transplant surgeon, Liver Unit, University Hospital Birmingham NHS Foundation Trust), Dr J W Ferguson (consultant hepatologist and honorary senior lecturer, Liver Unit, University Hospital Birmingham NHS Foundation Trust), Dr G Auzinger (consultant intensive care medicine, Liver Intensive Therapy Unit, Kings College Hospital London NHS Foundation Trust), Dr M Allison (consultant hepatologist, Liver Unit, Department of Medicine, Cambridge University Hospital NHS Foundation Trust), Dr J W Tomlinson (reader in endocrinology, Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham), H Manley (British Liver Trust), Dr K J Simpson (senior lecturer in hepatology, University of Edinburgh and honorary consultant physician, Scottish Liver Transplantation Unit, Royal Infirmary Edinburgh), Professor S G Hubscher (Leith Professor and Professor of Hepatic Pathology, University of Birmingham, and …

Renal function in patients undergoing transplantation for nonalcoholic steatohepatitis cirrhosis: Time to reconsider immunosuppression regimens?

Nonalcoholic fatty liver disease is an independent risk factor for chronic kidney injury (CKI), yet the impact of liver transplantation (LT) on renal function in this at‐risk group is not known. We compared the post‐LT renal function of patients with nonalcoholic steatohepatitis (NASH) and a matched comparison group. Forty‐eight consecutive patients who underwent transplantation for NASH between 2000 and 2008 in a single UK center were compared to non‐NASH patients who were matched by age, sex, Model for End‐Stage Liver Disease score, and estimated glomerular filtration rate (eGFR; calculated with the Modification of Diet in Renal Disease formula). In comparison with non‐NASH patients, NASH patients had a significantly lower eGFR 3 months after LT (eGFR difference = 8.85 mL/minute/1.73 m2, 95% confidence interval = 2.93‐14.77). After adjustments for the effects of the body mass index, tacrolimus levels, diabetes mellitus, hypertension, and hepatocellular carcinoma, the difference between the groups remained significant 3 months after LT (P = 0.001). These data were then analyzed at numerous time points after LT (6, 12, and 24 months), and the time did not significantly affect the difference between the groups (P = 0.17). Within 2 years, 31.2% of the NASH patients (15/48) had developed stage IIIb CKI, whereas only 8.3% of the non‐NASH patients (4/48) did (P = 0.009). In conclusion, this study has identified NASH as an independent risk factor for renal dysfunction after LT. Renal‐sparing immunosuppression regimens should be considered at the time of LT to reduce the development of kidney injury in NASH patients. The optimization of such regimens requires a prospective study. Liver Transpl 17:1292–1298, 2011.

Fulminant hepatic failure caused by tuberculosis.

A 54 year old Asian woman developed fulminant hepatic failure followed by renal failure. Because of a past history of possible tuberculosis, she was given antituberculous drugs. The chest x ray was normal. A transjugular liver biopsy showed caseating necrosis, granulomas, and acid fast bacilli indicative of miliary tuberculosis. Despite full supportive therapy, her condition deteriorated and she died. Postmortem examination showed widespread miliary tuberculosis; culture confirmed the presence of Mycobacterium tuberculosis. Tuberculosis causes fulminant hepatic failure rarely and only three cases have been described. In this, as with the other cases, hyponatraemia and hepatomegaly were features at presentation. This is the first report of treatment being given before death.

Review of methods for measuring and comparing center performance after organ transplantation

The assessment of outcomes after transplantation is important for several reasons: it provides patients with data so that they can make informed decisions about the benefits of transplantation and the success of the transplant unit; it informs commissioners that resources are allocated properly; and it provides clinicians reassurance that results are acceptable or, if they are not, provides early warning so that problems can be identified, corrections can be instituted early, and all interested parties can be reassured that scarce resources are used fairly. The need for greater transparency in reporting outcomes after liver transplantation and for comparisons both between and within centers has led to a number of approaches being adopted for monitoring center performance. We review some of the commonly used methods, highlight their strengths and weaknesses, and concentrate on methods that incorporate risk adjustment. Measuring and comparing outcomes after transplantation is complex, and there is no single approach that gives a complete picture. All those using analyses of outcomes must understand the merits and limitations of individual methods. When used properly, such methods are invaluable in ensuring that a scarce resource is used effectively, any adverse trend in outcomes is identified promptly and remedied, and best performers are identified; they thus allow the sharing of best practices. However, when they are used inappropriately, such measurements may lead to inappropriate conclusions, encourage risk‐averse behavior, and discourage innovation. Liver Transpl 16:1119–1128, 2010.

Outcomes of Liver Transplantation for Paracetamol (Acetaminophen)-Induced Hepatic Failure

Paracetamol (acetaminophen) hepatotoxicity, whether due to intentional overdose or therapeutic misadventure, is an indication for liver transplantation in selected cases. However, there is a concern that long‐term outcomes may be compromised by associated psychopathology that may predispose patients to further episodes of self‐harm or poor treatment adherence. We therefore undertook a retrospective analysis of patients transplanted for paracetamol‐induced fulminant hepatic failure (FHF) to determine their long‐term outcomes, psychiatric problems, and compliance and whether these issues could be predicted from pretransplant information. Records from patients undergoing liver transplantation for paracetamol‐associated liver failure in this unit and 2 comparison groups (patients undergoing liver replacement for FHF from other causes and for chronic liver diseases) were examined. Of 60 patients transplanted for paracetamol‐induced FHF between 1989 and 2007, 44 (73%) survived to discharge. Currently, 35 patients (58%) are surviving at an average of 9 years post‐transplantation. The incidence of psychiatric disease (principally depression) and 30‐day mortality were greatest in the paracetamol group, but for those who survived 30 days, there was no difference in long‐term survival rates between the groups. Adherence to follow‐up appointments and compliance with immunosuppression were lowest in the paracetamol overdose group. Poor adherence was not predicted by any identifiable premorbid psychiatric conditions. Two patients grafted for paracetamol FHF died from self‐harm (1 from suicide and 1 from alcoholic liver disease after 5 years). This study suggests that, notwithstanding the shortage of donor liver grafts, transplantation is an appropriate therapy in selected patients, although close follow‐up is indicated. Liver Transpl 15:1351–1357, 2009.

Finding a place for public preferences in liver allocation decisions.

Over the last decade there have been major advances in all aspects of liver transplantation with the consequence that the number of patients who could benefit from the procedure is increasing. As a result, the number of patients listed for liver transplantation is growing while the donor pool is remaining constant or even falling. The effect of this donor shortage is seen clearly both in Europe and in North America. For example, in North America data from UNOS shows that between 1988 and 1997 the number of cadaveric donor liver transplants rose from 1,713 to 4,100. The number of patients waiting for transplant rose over the same time from 616 to 9,647. This shortage of organs has tragic consequences. Although the proportion of patients dying on the waiting list is falling, the number of patients dying on the liver transplant waiting list increased from 196 to 1,129 over this same period of time.

Implications of changing the minimal survival benefit in liver transplantation

The limited availability of livers donated by deceased donors for transplantation means that not everyone who might benefit from the procedure can receive a graft, so any selection and allocation system must have clearly defined goals. The United Kingdom, in common with many other countries, has adopted a minimum benefit criterion of a greater than 50% probability of survival 5 years after transplantation. We investigated the impact of changing this minimum benefit criterion on a case mix of listed patients. The analysis was based on 5330 adult elective patients who underwent transplantation with livers from donation after brain death donors between January 1994 and December 2007. We examined the impact of balancing the number of registrations on the list with the number of available donor livers while allowing a 10% mortality rate and found that this would require a survival threshold of at least 74% at 5 years. According to historical data, the application of this more stringent criterion would significantly reduce the eligibility of older and nonwhite patients and patients with hepatocellular carcinoma or hepatitis C virus infections. Thus, if such undesirable restrictions on access to liver transplantation are to be avoided, we must consider alternative strategies such as the acceptance of higher transplant list mortality. Liver Transpl, 2012.