Liver Transplantation for Primary Sclerosing Cholangitis (PSC) With or Without Inflammatory Bowel Disease (IBD)-A European Society of Organ Transplantation (ESOT) Consensus Statement.

Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of inflammatory bowel disease (IBD) and a lead indication for liver transplantation (LT) in the western world. In this article, we present a Consensus Statement on LT practice, developed by a dedicated Guidelines' Taskforce of the European Society of Organ Transplantation (ESOT). The overarching goal is to provide practical guidance on commonly debated topics, including indications and timing of LT, management of bile duct stenosis in patients on the transplant waiting list, technical aspects of transplantation, immunosuppressive strategies post-transplant, timing and extension of intestinal resection and futility criteria for re-transplantation.

The effect on consent rates for deceased organ donation in Wales after the introduction of an opt-out system.

Organ transplantation saves and transforms lives. Failure to secure consent for organ retrieval is widely regarded as the single most important obstacle to transplantation. A soft opt-out system of consent for deceased organ donation was introduced into Wales in December 2015, whilst England maintained the existing opt-in system. Cumulative data on consent rates in Wales were compared with those in England, using a two-sided sequential procedure that was powered to detect an absolute difference in consent rates between England and Wales of 10%. Supplementary risk-adjusted logistic regression analysis examined whether any difference in consent rates between the two nations could be attributed to variations in factors known to influence UK consent rates. Between 1 January 2016 and 31 December 2018, 8192 families of eligible donors in England and 474 in Wales were approached regarding organ donation, with overall consent rates of 65% and 68%, respectively. There was a steady upward trend in the proportion of families consenting to donation after brain death in Wales as compared with England and after 33 months, this reached statistical significance. No evidence of any change in the donation after circulatory death consent rate was observed. Risk-adjusted logistic regression analysis revealed that by the end of the study period the probability of consent to organ donation in Wales was higher than in England (OR [95%CI] 2.1 [1.26-3.41]). The introduction of a soft opt-out system of consent in Wales significantly increased organ donation consent though the impact was not immediate.

Donors With Immune Thrombocytopenia: Do They Pose a Risk to Transplant Recipients?

Transplant-mediated alloimmune thrombocytopenia (TMAT) from donors with immune thrombocytopenia (ITP) can result in significant bleeding complications in the recipient. The risk to a recipient of TMAT if they receive an organ from a donor with ITP is unknown. The outcomes of recipients of organs from deceased donors with ITP recorded in the UK Transplant Registry between 2000 and 2015 were reviewed. Twenty-one deceased organ donors had a predonation diagnosis of ITP. These donors were significantly more likely to have died from intracranial hemorrhage than were all other deceased organ donors (85% vs. 57%, p < 0.001). Organs from donors with ITP resulted in 49 organ transplants (31 kidney, 14 liver, four heart), with only one case of TMAT, which occurred in a liver transplant recipient and resulted in death from bleeding complications 18 days posttransplantation. The recipient of a kidney from the same organ donor was not affected. Unadjusted 5-year patient and graft survival was significantly worse for liver transplant recipients from donors with ITP compared with liver transplant recipients from donors without ITP (64% vs. 85%, p = 0.012). Organs from donors with ITP may be considered for transplantation, but livers should be used with caution.

Estimated risk of cancer transmission from organ donor to graft recipient in a national transplantation registry.

BACKGROUND: Transplanted organs carry the risk of inadvertent donor cancer transmission. Some cancers in organ donors have been classified as being associated with a high or unacceptable risk, but the evidence for such recommendations is scanty. METHODS: The risk of cancer transmission from donors characterized as high or unacceptable risk was studied by analysing transplant and cancer registry data. Donors and recipients from England (1990-2008) were identified from the UK Transplant Registry. Cancer details were obtained from cancer registries and classified using guidelines from the Council of Europe and Organ Procurement and Transplantation Network/United Network for Organ Sharing. RESULTS: Of 17,639 donors, 202 (1.1 per cent) had a history of cancer, including 61 donors with cancers classed as having an unacceptable/high risk of transmission. No cancer transmission was noted in 133 recipients of organs from these 61 donors. At 10 years after transplantation, the additional survival benefit gained by transplanting organs from donors with unacceptable/high-risk cancer was 944 (95 per cent confidence interval (c.i.) 851 to 1037) life-years, with a mean survival of 7.1 (95 per cent c.i. 6.4 to 7.8) years per recipient. CONCLUSION: Strict implementation of present guidelines is likely to result in overestimation of cancer transmission risk in some donors. Organs from some donors with cancers defined as unacceptable/high risk can be used safely.

Standardized deceased donor kidney donation rates in the UK reveal marked regional variation and highlight the potential for increasing kidney donation: a prospective cohort study†.

BACKGROUND: The UK has implemented a national strategy for organ donation that includes a centrally coordinated network of specialist nurses in organ donation embedded in all intensive care units and a national organ retrieval service for deceased organ donors. We aimed to determine whether despite the national approach to donation there is significant regional variation in deceased donor kidney donation rates. METHODS: The UK prospective audit of deaths in critical care was analysed for a cohort of patients who died in critical care between April 2010 and December 2011. Multivariate logistic regression was used to identify the factors associated with kidney donation. The logistic regression model was then used to produce risk-adjusted funnel plots describing the regional variation in donation rates. RESULTS: Of the 27 482 patients who died in a critical care setting, 1528 (5.5%) became kidney donors. Factors found to influence donation rates significantly were: type of critical care [e.g. neurointensive vs general intensive care: OR 1.53, 95% confidence interval (CI) 1.34-1.75, P<0.0001], patient ethnicity (e.g. 'Asian' vs 'white': OR 0.17, 95% CI 0.11-0.26, P<0.0001), age (e.g. age >69 vs age 18-39 yr: OR 0.2, 0.15-0.25, P<0.0001), and cause of death [e.g. 'other' (excluding 'stroke' and 'trauma') vs 'trauma': OR 0.04, 95% CI 0.03-0.05, P<0.0001]. Despite correction for these variables, kidney donation rates for the 20 UK kidney donor regions showed marked variation. The overall standardized donation rate ranged from 3.2 to 7.5%. Four regions had donation rates of >2 standard deviations (sd) from the mean (two below and two above). Regional variation was most marked for donation after circulatory death (DCD) kidney donors with 9 of the 20 regions demonstrating donation rates of >2 sd from the mean (5 below and 4 above). CONCLUSIONS: The marked regional variation in kidney donation rates observed in this cohort after adjustment for factors strongly associated with donation rates suggests that there is considerable scope for further increasing kidney donation rates in the UK, particularly DCD.

Comparison of the incidence of malignancy in recipients of different types of organ: a UK Registry audit.

An increased incidence of malignancy is an established complication of organ transplantation and the associated immunosuppression. In this study on cancer incidence in solid organ transplant recipients in Britain, we describe the incidence of de novo cancers in the allograft recipient, and compare these incidences following the transplantation of different organs. Data in the UK Transplant Registry held by NHS Blood and Transplant (NHSBT) were linked with data made available by the cancer registries in England, Scotland and Wales. Incidence rates in the transplanted population were then compared with the general population, using standardized incidence ratios matched for age, gender and time period. The 10-year incidence of de novo cancer in transplant recipients is twice that of the general population, with the incidence of nonmelanoma skin cancer being 13 times greater. Nonmelanoma skin cancer, cancer of the lip, posttransplant lymphoproliferative disease and anal cancer have the largest standardized incidence ratios, but the incidence of different types of malignancy differs according to the organ transplanted. Patterns in standardized incidence ratios over time since transplantation are different for different types of transplant recipient, as well as for different malignancies. These results have implications for a national screening program.

Liver transplantation for alcoholic liver disease in Europe: a study from the ELTR (European Liver Transplant Registry).

Alcohol-related liver disease (ALD) is one of the most common indications for liver transplantation (LT). Long-term outcome after LT for ALD versus other etiologies is still under debate. The aim of this study was to compare outcome after LT of patients with ALD, viral (VIR), and cryptogenic cirrhosis. Donor, graft and recipient ELTR variables were analysed in transplants for alcoholic and nonalcoholic cirrhosis (1988-2005) and were correlated with patient survival. Causes of death and/or graft failure were compared between groups. Nine thousand eight hundred eighty ALD, 10,943 VIR, 1478 ALD+VIR and 2410 cryptogenic (CRYP) liver transplants were evaluated. One, 3, 5 and 10 years graft survival rates after LT in ALD patients were 84%, 78%, 73%, 58%, significantly higher than in VIR and CRYP (p=0.04, p=0.05). By multivariate analysis, ALD+VIR (RR 1.14) and viral alone (RR 1.06) were significant risk factors for mortality. De novo tumors, cardiovascular and social causes were causes of death/graft failure in higher percentage in ALD groups versus other etiologies. LT for ALD cirrhosis has a favorable outcome, however, hepatitis C virus co-infection seems to eliminate this advantage. Screening for de novo tumors and prevention of cardiovascular complications are essential to provide better long-term results.

Delayed introduction of reduced-dose tacrolimus, and renal function in liver transplantation: the 'ReSpECT' study.

We report a multicenter, prospective, randomized, open-label trial investigating the effect of lower levels and delayed introduction of tacrolimus on renal function in liver transplant recipients. Adult patients with good renal function undergoing primary liver transplant were randomized to either: group A (standard-dose tacrolimus [target trough levels >10 ng/mL] and corticosteroids; n = 183); group B (mycophenolate mofetil [MMF] 2g/day, reduced-dose tacrolimus [target trough levels

Chronic liver allograft dysfunction.

Approximately 90% of liver transplant patients are alive after 1 year and 75% after 5 years with the majority leading full and near-normal lives. However, although early mortality rates after transplantation have fallen dramatically over the last 2 decades, the rates of late graft loss and patient death have remained constant. Thus, understanding of the causes of graft and patient failure is essential to improve long-term outcomes. In the early days after liver transplantation, ischemia and reperfusion injuries predominate, with acute cellular rejection relatively common in first 3 months. Thereafter, the causes of graft dysfunction are variable with disease recurrence as a major cause of graft loss. In this review, we discuss causes of graft dysfunction after 6 months.

Selection of patients for liver transplantation and allocation of donated livers in the UK.

BACKGROUND: The increasing shortfall between the number of patients who would benefit from liver transplantation and the availability of donor livers means that rationing has to occur. The processes of selection of patients for transplantation and for allocation of donor livers should be done according to ethical and, where possible, evidence-based criteria so that there is clarity and that the competing requirements of equity, justice, utility and benefit can be balanced. METHODS: To achieve these goals for patients in the United Kingdom in need of transplantation, we have developed guidelines for the selection of patients to the national waiting list based on the risk of death without a transplant and the ability of the procedure to improve the recipient's quality of life. Guidelines have been developed for both those with acute liver failure and chronic liver disease. Allocation will depend on matching of the donor liver to the recipient. RESULTS: The proposed system, to be introduced into the UK compares with some other systems, where different models for selection and allocation have been introduced.

Confirmation of specificity of reactivity in a solid phase ELISA for the detection of hepatitis E viral antigen improves utility of the assay.

Genotype 3 hepatitis E virus (HEV) can lead to persistent infections in immunocompromised hosts. A recently available commercial assay for the detection of HEV antigen (HEV-Ag ELISA, Wantai diagnostics) may enable the study of HEV-Ag dynamics in such persistent infections, however currently there is no confirmatory test available. We generated a putative neutralising reagent from a pool of four convalescent blood donor samples and explored neutralising activity against HEV antigens from clinical samples, HEV tissue-culture and virus-like particles. Using this neutralisation method we were able to differentiate true reactivity from non-specific reactivity in plasma, stool and urine samples. This could also facilitate the introduction of HEV-Ag detection as a screening assay or the study of HEV-Ag in different body fluids.

Human intrahepatic biliary epithelial cells proliferate in vitro in response to human hepatocyte growth factor.

In previous studies, intrahepatic human biliary epithelial cells (BEC) were isolated in high purity. However, these cells demonstrated only limited growth responses. Here we report that human BEC proliferate in response to human hepatocyte growth factor (hHGF), retain BEC-specific phenotype, and can be serially passaged. BEC showed dose-dependent growth in response to 0.01-100 ng/ml hHGF. The maximum S-phase labeling index reached 40% with half-maximal stimulation at 1 ng/ml. The response of cells from normal and primary biliary cirrhotic liver to hHGF was similar. Cultures were immunostained with specific antibodies and then processed for [3H]thymidine autoradiography. Proliferating cells expressed BEC-specific markers (HEA125 and CK-19), but were negative for desmin and factor VIII-related antigen. Occasional vimentin-positive cells were observed, but these were nonproliferative. In conclusion, cells responding to hHGF were clearly BEC in origin. The observation that HGF is mitogenic for BEC as well as hepatocytes has important implications. First, greater yields of intrahepatic BEC are available for subsequent studies of the pathogenesis and etiology of diseases of the biliary epithelium. Secondly, some means of regulating the cellular response to HGF in vivo must operate, in that HGF levels rise early after partial hepatectomy and yet BEC proliferate 24 h later than hepatocytes.

Role of Religion in Organ Donation-Development of the United Kingdom Faith and Organ Donation Action Plan.

At a national policy level, the United Kingdom is at the forefront of recognizing the role of faith and its impact on organ donation. This is demonstrated by the recommendations of the Organ Donation Taskforce, National Institute for Clinical Excellence guidelines on organ donation, All-Party Parliamentary Kidney Group, and National Black, Asian and Minority Ethnic Taskforce Alliance. Evidence to date shows that further thought is required to ensure the active engagement of faith communities with organ donation in the UK. The "Taking Organ Transplantation to 2020" strategy was launched in July 2013 by National Health Service Blood and Transplant (NHSBT) in collaboration with the Department of Health and Welsh, Scottish, and Northern Irish governments and seeks to increase the number of people, from all sections of the UK's multiethnic and multifaith population, who consent to and authorize organ donation in their life. NHSBT seeks to work in partnership with faith leaders and this culminated in a Faith and Organ Donation Summit. Faith leaders highlight that there is a need for engagement at both national and local levels concerning organ donation as well as diagnosis and definition of death.

The inter-relationship of symptom severity and quality of life in 2055 patients with primary biliary cholangitis.

BACKGROUND: Age at presentation with primary biliary cholangitis (PBC) is associated with differential response to ursodeoxycholic acid (UDCA) therapy. Younger-presenting patients are less likely to respond to treatment and more likely to need transplant or die from the disease. PBC has a complex impact on quality of life (QoL), with systemic symptoms often having significant impact. AIM: To explain the impact of age at presentation on perceived QoL and the inter-related symptoms which impact upon it. METHODS: Using the UK-PBC cohort, symptoms were assessed using the PBC-40 and other validated tools. Data were available on 2055 patients. RESULTS: Of the 1990 patients reporting a global PBC-QoL score, 66% reported good/neutral scores and 34% reported poor scores. Each 10-year increase in age at presentation was associated with a 14% decrease in risk of poor perceived QoL (OR = 0.86, 95% CI: 0.75-0.98, P < 0.05). All symptom domains were similarly age-associated (P < 0.01). Social dysfunction was the symptom factor with the greatest impact on QoL. Median (interquartile range) PBC-40 social scores for patients with good perceived QoL were 18 (14-23) compared with 34 (29-39) for those with poor QoL. CONCLUSION: The majority of patients with primary biliary cholangitis do not feel their QoL is impaired, although impairment is reported by a sizeable minority. Age at presentation is associated with impact on perceived QoL and the symptoms impairing it, with younger patients being more affected. Social dysfunction makes the greatest contribution to QoL impairment, and it should be targeted in trials aimed at improving life quality.

The effect of bile salts on human vascular endothelial cells.

The uptake and release of radiochromium from adult human vascular endothelial cells in culture was employed to determine the relative toxicity of different bile salts. Endothelial cells after pre-incubation with 51Cr for 18 h were incubated with bile salts for 24 h and percentage chromium release was taken as a measure of toxicity to cells. Lithocholic acid (LC) (potassium salt) was cytotoxic at concentrations greater than 50 microM. However, LC glucuronide, sulfate and the beta-epimer were progressively less toxic with toxicity seen at concentrations of 60, 110 and 180 microM, respectively. The greatest cytotoxic effect was observed with glycolithocholic acid (GLC) (potassium salt) which was toxic at every concentration tested (20-200 microM). Sulfation abolished the toxic effect of GLC. At the concentrations employed for the assay (between 20 and 240 microM) GLC sulfate (disodium salt), taurolithocholic acid sulfate (disodium salt), cholic acid (sodium salt), glycocholic acid (sodium salt), deoxycholic acid (sodium salt) and ursodeoxycholic acid (sodium salt) were not cytotoxic. The 51Cr release cytotoxicity assay was validated with lactate dehydrogenase leakage from endothelial cells with a good correlation (r = 0.87). These data confirm in a human cellular system that LC and its conjugates were the most toxic of the bile salts tested and explains its pathophysiological importance in hepatobiliary disease. It also suggests that biotransformation by either sulfation or beta-epimerisation of bile salts especially of LC, as occurs in patients with intrahepatic or extrahepatic biliary obstruction or severe cholestasis, is hepatoprotective.

Long-term immunosuppression for prevention of nonviral disease recurrence.

The choice of immunosuppressive regime used after liver transplantation depends on many factors, which should include the effect of disease recurrence; recurrence of disease after liver transplantation may be affected by the degree and type of immunosuppression used and recurrent disease may affect patient and graft survival. For autoimmune diseases, recurrence of primary biliary cirrhosis develops sooner and more rapidly in those on tacrolimus compared with cyclosporine, but graft loss from recurrent disease is uncommon; recurrence rates of primary sclerosing cholangitis is unaffected by immunosuppressive regimes and recurrence of autoimmune hepatitis may be reduced by prescription of corticosteroids. Whether the immunosuppressive regime affects the pattern of hepatocellular carcinoma recurrence is uncertain. It is probable that the use of calcineurin inhibitor does not have a significant effect and inhibitors of TOR may have an anti-cancer effect, but this still has to be shown clinically. Most metabolic diseases are not affected by the choice of immunosuppression, although recurrence of sarcoidosis may be prevented by corticosteroids.

Expression and function of thyroid hormone receptor variants in normal and chronically diseased human liver.

As the liver represents a major target organ for thyroid hormone action, we compared the expression of thyroid hormone receptor (TR) alpha and beta variants in normal human liver and liver affected by primary biliary cirrhosis, sclerosing cholangitis, cryptogenic cirrhosis, and alcoholic cirrhosis (n = 6 in each group). Western blot analysis using specific polyclonal antibodies to alpha 1 or beta 1 TRs or to the related non-T3-binding c-erbA alpha 2 variant revealed abundant expression of TRs in normal and diseased liver, with no difference in size or abundance of TR proteins. Immunocytochemistry likewise revealed abundant nuclear expression of TR proteins in normal and diseased liver, with similar patterns and intensity of staining. Despite abundant TR protein expression, Northern blot hybridization of polyadenylated ribonucleic acid (RNA; 10 micrograms) to TR complementary DNAs revealed only a weak signal for c-erbA alpha 2 messenger RNA (mRNA). Comparison of the level of expression of the thyroid hormone-regulated mRNAs encoding T4-binding globulin, sex hormone-binding globulin, cortisol-binding globulin, and transthyretin in normal and diseased tissue revealed no significant difference, suggesting that hepatocellular expression of these mRNAs is maintained in chronic liver disease despite a marked reduction in circulating T3 concentrations.