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.

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.

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

Clinical trial: randomized controlled study of zidovudine and lamivudine for patients with primary biliary cirrhosis stabilized on ursodiol.

BACKGROUND: A human betaretrovirus has been characterized in patients with primary biliary cirrhosis (PBC). Uncontrolled studies using combination anti-retroviral therapy have reported significant biochemical and histological improvement. AIM: To conduct a double blind, randomized controlled trial as a proof of principal to link infection with PBC. METHODS: Fifty-nine patients with an alkaline phosphatase level>1.5 upper limits of normal stabilized on ursodeoxycholic acid therapy were randomized to either 300 mg zidovudine and 150 mg lamivudine B.I.D. or placebo for 6 months. RESULTS: None of the patients normalized alkaline phosphatase and no significant differences were observed in normalizing serum aminotransferase levels. Significant differences were observed in the antiviral versus placebo arms with improvements in serial alkaline phosphatase (p<0.04), ALT (p<0.03) and AST (p<0.04) as well as clinical score (p<0.02). After 6 months, 25% of patients in the placebo arm and 4% in the antiviral arm had evidence of virus in serum. CONCLUSIONS: The study endpoints for normalizing hepatic biochemistry were too stringent to show efficacy for zidovudine and lamivudine therapy despite the demonstrable impact on clinical and biochemical improvement. Accordingly, more potent anti-viral regimens will be required to confirm the efficacy of antiviral therapy in PBC patients with human betaretrovirus infection.

Delayed hepatic artery thrombosis in adult orthotopic liver transplantation-a 12-year experience.

BACKGROUND: Although the clinical features of early hepatic artery thrombosis (HAT) are well defined, the features of delayed (more than 4 weeks after transplantation) hepatic artery thrombosis are less clearly defined. The aim of our study was to identify risk factors, clinical presentation, and outcome of management of delayed hepatic artery thrombosis (HAT) after liver transplant (LTx). METHODS: An analysis of prospectively collected data of all patients transplanted from 1986 to 1998 was performed. The importance of recipient (age, sex, primary indication for LTx, cytomegalovirus status, and intraabdominal sepsis) and donor factors (donor age, cold ischemia time, and donor cytomegalovirus status), modes of presentation, and outcome of treatment (biliary reconstruction/stenting, regraft, vascular reconstruction, observation) were analyzed. RESULTS: Delayed HAT was seen in 31/1097 adult LTx recipients (incidence 2.8%). No recipient or donor factors were identified as risk factors. A total of 16 patients were symptomatic at presentation (HAT diagnosed on abdominal ultrasound). Six patients had recurrent episodes of cholangitis, four had cholangitis with a stricture, four had cholangitis and intrahepatic abscesses, and two had bile leaks. Biliary reconstruction was done in six patients (all of whom subsequently required a regraft), vascular reconstruction was performed in two patients (one regrafted and one died shortly after), four patients with cholangitis and stricture on presentation had a biliary stent (all four were later regrafted). A total of 16 patients were regrafted, 9 are alive, 5 died within 6 months (septic at time of LTx), 1 died after 1 year, and 1 died after 2 years. Fifteen patients were asymptomatic and detected on routine screening. 5 have remained asymptomatic and are still alive, 1 developed a biliary stricture that was stented and is alive 105 months later, 4 had recurrence of the original disease, 3 developed progressive graft failure and were listed for transplant but died before regraft due to overwhelming sepsis and hepatic encephalopathy. Two patients died due to nonbiliary sepsis. CONCLUSIONS: Delayed HAT is a rare complication of LTx that may present with biliary sepsis, or remain asymptomatic. Biliary or vascular reconstructions do not increase graft survival. Of the patients who were clinically silent on presentation, 20% developed progressive graft failure requiring a second transplant. A total of 33% survived in the long-term without a second transplant. Ongoing severe sepsis at the time of regraft results in poor survival.

Morphogenesis of primary human biliary epithelial cells: induction in high-density culture or by coculture with autologous human hepatocytes.

Although the control of biliary ductular morphogenesis has received some attention particularly using isolated rat biliary epithelial cell models, the regulation of human bile duct formation is not well defined. In the present study, using a 3-dimensional culture model comprising primary human biliary epithelial cells (BECs) and coculture with primary human hepatocytes, we have sought to define the factors involved. We have shown that primary human BECs can be expanded on collagen gels in the absence of growth factors or serum. When plated in high density in double collagen gels, BECs established 3-dimensional structures that subsequently developed into well differentiated polarized luminal ducts. This morphogenic response occurred in the absence of hepatocyte growth factor (HGF) and epidermal growth factor. Strikingly, the addition of growth factors (in the presence of serum) resulted in loss of polarity although the cells retained growth responses to both factors. Coculture of BECs with autologous human hepatocytes enhanced the ability of low-density BECs to undergo ductulogenesis. This effect was mimicked by addition of conditioned medium from previous hepatocyte-BEC cocultures. These findings indicate that for human biliary ductular morphogenesis, epithelial cell-cell interactions are required but that mesenchymally derived factors such as HGF may not be important.

A prospective randomized study of preoperative nutritional supplementation in patients awaiting elective orthotopic liver transplantation.

BACKGROUND: Poor nutritional status is common among patients awaiting orthotopic liver transplantation and is associated with poor outcome. METHODS: This prospective randomized controlled trial examined the effect of pretransplant nutritional supplementation on the outcome of patients undergoing liver transplantation. Of 82 consecutive patients with mid-arm muscle circumference <25th percentile, 42 received enteral supplementation, and the remainder acted as the control group. The supplemented group received a calorie-dense enteral feed taken daily (in addition to diet) until transplantation. Nutritional status was monitored by upper arm anthropometric measurements and handgrip strength. Dietary intake was calculated from 5-day food diaries. RESULTS: Supplementation improved mid-arm circumference, mid-arm muscle circumference, and grip strength. Pretransplant nutritional status was not associated with posttransplant sepsis or major complications. Preoperative grip strength of <85% of normal values was predictive of increased incidence of posttransplant major complications. Supplementation did not affect outcome, although there were more deaths in the control group (seven deaths before and two deaths after transplant) than there were in the supplemented group (two deaths before and three deaths after transplant). There was no difference in overall survival (P = 0.075). CONCLUSIONS: Enteral supplementation improved some parameters of nutritional status pretransplant. Dietary intake of patients in the two groups was similar at transplant. Nutritional supplementation has not increased nutritional intake, although this may reflect the importance of regular dietetic input and support, rather than suggesting that nutritional supplementation is ineffective. Supplementation had no effect on outcome of liver transplantation.

Characterization and isolation of ductular cells coexpressing neural cell adhesion molecule and Bcl-2 from primary cholangiopathies and ductal plate malformations.

It has recently been shown that reactive bile ductules display neuroendocrine features, including immunoreactivity for the neural cell adhesion molecule (NCAM). In this study we have compared the immunohistochemical expression of NCAM with that of HEA-125 (biliary specific) and LKM-1 (hepatocyte specific) and other markers relevant to morphogenesis (Bcl-2, EMA) and cell proliferation (Ki-67) in cryostat sections from different chronic liver diseases and from fetal livers at different gestational ages. In parallel, viable NCAM-positive ductular cells were purified from collagenase digests of cirrhotic livers by immunomagnetic separation and characterized by immunocytochemistry and transmission electron microscopy. We demonstrated that reactive ductules with atypical morphology coexpressed NCAM and Bcl-2 and were found mainly in congenital diseases associated with ductal plate malformation and in primary cholangiopathies. On the contrary, reactive ductules with typical morphology were negative for NCAM/Bcl-2 and positive for EMA. Reactive ductules coexpressing NCAM/Bcl-2 were negative for the proliferation marker Ki-67 and appeared to be directly connected with periportal hepatocytes. In fetal livers NCAM/Bcl-2 was transiently expressed during the early developmental stages of ductal plate (10-16 weeks) and started to disappear as the ductal plate began duplicating. NCAM-positive ductal plate cells were Ki-67 negative, becoming positive in duplicated segments. Thus the histogenesis of ductular reactive cells seems to recapitulate the early stages of biliary ontogenesis. In primary cholangiopathies and ductal plate malformations, these cells do not appear to maturate further, and thus abundant ductular structures coexist with vanishing mature ducts. These NCAM-positive ductular cells were immunopurified from patients with chronic cholestatic liver diseases and showed ultrastructural features consistent with a less differentiated phenotype than mature cholangiocytes. These isolated cells represent a useful model for in vitro studies.

Effect of sodium benzoate in the treatment of atypical nonketotic hyperglycinaemia.

A 6-month-old girl presented with hypotonia and mild psychomotor retardation. Subsequently, an atypical manifestation of a nonketotic hyperglycinaemia was diagnosed, confirmed by significantly reduced activity of the glycine cleavage system in the liver tissue. After the patient developed hypsarrhythmia and had a single cerebral seizure, treatment with both sodium benzoate and dextromethorphan was started. During the following year, the girl was free of seizures with improvement of the EEG activity and showed retarded but continuously progressing psychomotor development. At the age of 20 months she began to walk freely but had generalized muscular hypotonia and moderate mental retardation. Discontinuation of dextromethorphan medication after one year of treatment did not change the clinical and electroencephalographic status. However, after cessation of sodium benzoate therapy, epileptic activity in the EEG and behavioural changes occurred. These changes disappeared promptly after sodium benzoate therapy was reinstituted. Thus, this case of mild atypical nonketotic hyperglycinaemia with only moderate psychomotor retardation and without epilepsy benefited from treatment with sodium benzoate in terms of electroencephalographic and behavioural changes.

Poor outcome in patients with diabetes mellitus undergoing liver transplantation.

BACKGROUND: Relatively few studies have examined the influence of pretransplant diabetes on survival after an orthotopic liver transplant (OLT), and those published to date show only minor increases in infection rates among diabetics and no increase in mortality. METHODS: We examined the effect of diabetes mellitus on survival after OLT. 1005 adults underwent OLT between 1982 and May 1997. Seventy-eight patients with pretransplant diabetes mellitus (7.8% of all OLT, 38 insulin treated, 25 tablet treated, 15 diet controlled) were identified and compared with controls matched for age, sex, and date of first transplant and also with all nondiabetic adult liver recipients undergoing OLT during the same period. RESULTS: In patients undergoing OLT survival was worse in diabetics than in the comparison group (P=0.002) and vs. all adult nondiabetics undergoing (n=927) (P=0.004); in diabetics with alcoholic liver disease (ALD) vs. all nondiabetics with alcoholic liver disease (P= <0.0001); and in insulin-treated compared with non-insulin-treated diabetics (P=0.05). Multivariate analysis showed type of diabetes (P=0.001) and ALD (P=0.024) to be the most significant independent variables adversely affecting survival. Survival in diabetics undergoing OLT could be further stratified according to whether diabetics were insulin treated. CONCLUSIONS: Poorer outcome in the diabetics undergoing OLT, particularly in those with ALD, suggests the need for a more detailed pre-OLT assessment of these patients, particularly those with insulin and tablet controlled diabetes.

Immunopathology of primary biliary cirrhosis.

A major advance in the study of primary biliary cirrhosis was identification of the major B-cell auto-antigen as the mitochondrial enzyme pyruvate dehydrogenase dihydrolipoamide acetyltransferase (PDC-E2). Subsequent studies revealed that PDC-E2 also contained epitopes recognized by patients' T cells. Furthermore, aberrant expression of MHC class II, intercellular adhesion molecules, lymphocyte co-stimulatory molecules and B-cell epitopes of PDC-E2 was observed on patients' biliary epithelium, supporting the concept that biliary epithelial cells are the target of a focused autoimmune reaction. Changes in distribution of auto-antigen on biliary epithelium and the presence of auto-antibody in patient's serum have both been shown to occur very early in the natural history of primary biliary cirrhosis, suggesting an intimate role for these molecules in immunopathogenetic mechanisms.

Chronic renal failure following liver transplantation: a retrospective analysis.

BACKGROUND: Liver transplant recipients are at risk of chronic renal disease, principally as a result of nephrotoxicity of the commonly used immunosuppressive agents cyclosporine and tacrolimus. We have investigated the incidence of chronic renal failure and its risk factors in our transplant population, which was treated predominantly with cyclosporine. METHODS: A single-center retrospective study was done of 883 consecutive adult patients receiving a first liver transplant between 1982 and 1996. Potential risk factors for the development of chronic renal failure were recorded, including serial measurements of cyclosporine therapy and renal function. RESULTS: Severe chronic renal failure (serum creatinine level >250 microM/L for at least 6 months) developed in 25 patients, representing 4% of patients surviving 1 year or more. Twelve of these patients developed end-stage renal failure and mortality was 44%. The predominant cause of renal failure was cyclosporine nephrotoxicity. Serum creatinine as early as 3 months after surgery was strongly associated with the eventual development of severe chronic renal failure (P=0.001), and this group could be further subdivided into two groups with differing risk factors. The first group had early (<1 year) renal dysfunction, with older age (P=0.03), cytomegalovirus infection (P=0.03), need for perioperative renal replacement therapy (P=0.06), and regrafting (P=0.06) as risk factors for eventual renal failure; the second group had late-onset (>1 year) renal dysfunction, with cyclosporine levels at 1 month after surgery (P=0.007) and daily and cumulative cyclosporine dosage at 5 years (P=0.01 for both) as risk factors. CONCLUSIONS: With improved survival of liver transplant recipients, chronic renal failure has become an important cause of morbidity and is associated with a high mortality. Many patients at risk of severe chronic renal failure may be identified at an early stage. Treatment regimens that avoid or prevent cyclosporine-induced nephrotoxicity are urgently required for this population.

Perioperative parenteral and enteral nutrition for patients undergoing orthotopic liver transplantation. Results of a questionnaire from 16 European transplant units.

The present clinical experience in perioperative nutrition for patients undergoing orthotopic liver transplantation was evaluated by a questionnaire, answered by 16/21 European transplant units (76.1%). There is agreement, that malnutrition reflects per se the severity of chronic liver disease and should be not considered, in general, to exclude patients from the transplant waiting list. Most centers administer postoperative nutrition without difference to other patients after gastrointestinal major surgery. A combination of parenteral and enteral nutrition is preferred. Experience with preoperative nutritional support and use of new immunomodulating substances is rather limited.

Health-related quality of life following liver transplantation.

The objectives of this study were to report on the health-related quality of life (QoL) experienced by patients following liver transplantation and to investigate the factors associated with its variation. A questionnaire comprising the SF-36 and EuroQol EQ-5D instruments was sent by post to 147 patients who had received a liver transplant, indicated by a chronic liver disease, in the previous 8 years. The scores of the respondents were compared to population norm scores. The variation in both the SF-36 and EQ-5D scores was explored. Many liver transplant patients experienced most satisfactory QoL levels post-transplantation although, in general terms, the levels were poorer than those seen in the general population. The variation in the post-transplant health-related QoL scores was found to be associated with a number of pre-transplant factors: disease severity (proxied by Child Pugh class), disease duration at the time of transplantation and liver transplant history (whether the patient had received a single or multiple transplants). In making clinical decisions about the use of transplantation for chronic liver diseases, consideration should be given to the key factors likely to affect subsequent health-related QoL.

The human biliary epithelial cell plasma membrane antigen in primary biliary cirrhosis: pyruvate dehydrogenase X?

BACKGROUND & AIMS: Patients with primary biliary cirrhosis (PBC) have autoantibodies that react with components of mitochondrial multienzyme complexes. In addition to binding to mitochondria, patients' autoantibodies to the assumed major autoantigen pyruvate dehydrogenase complex (PDC) dihydrolipoamide acetyltransferase (E2) bind to the plasma membrane of biliary epithelial cells (BECs) specifically in PBC. The aim of this study was to characterize BEC plasma membrane antigens recognized by patients' autoantibodies in PBC. METHODS: Antigens prepared from intracellular and plasma membrane-enriched fractions of BECs purified from PBC and control liver were immunoblotted with anti-PDC. RESULTS: In the intracellular fraction, anti-PDC recognized BEC protein bands corresponding to the molecular weight value of E2 and X components of human heart PDC on Western blots. No difference was observed between PDC-E2 in BECs from PBC and controls. However, in PBC but not controls, a 50-kilodalton antigen was detected in the plasma membrane-enriched fraction. This antigen comigrated with component X of purified human heart PDC and was recognized by antibodies specific for PDC-X. CONCLUSIONS: The data suggest that PDC-X or a cross-reactive 50-kilodalton antigen is the BEC plasma membrane antigen recognized by patients' autoantibodies in PBC. Furthermore, this antigen, rather than PDC-E2, may be a major B-cell target antigen in PBC.

A positive crossmatch in liver transplantation--no effect or inappropriate analysis? A prospective study.

BACKGROUND: Controversy over the relationship of preformed lymphocytotoxic antibodies and liver graft outcome remains. Because graft loss associated with preformed lymphocytotoxic antibodies probably occurs early after transplant, analysis of long-term survival is of questionable value. We therefore prospectively analyzed the effect on short- and long-term graft survival of the presence of lymphocytotoxic alloantibody in 207 primary adult liver allograft recipients. METHODS: Pretransplant serum was tested for donor-specific lymphocytotoxic antibodies and panel-reactive antibodies (PRA) using donor splenic lymphocytes and lymphocytes obtained for routine tissue typing. RESULTS: A positive crossmatch was detected in 24 recipients (11.5%): T-cell positive in 11 recipients and B-cell positive in 13 recipients. PRA were detected in 68 of 179 recipients tested (37.4%). High T-cell PRA (>55%) was detected in 17 recipients, and high B-cell PRA was detected in 20 recipients. Low PRA (<15%) against T cells was detected in 19 recipients and against B cells in 24 recipients. Graft failures occurred in 5 of 24 (21%) crossmatch-positive recipients and in 7 of 172 (4%) crossmatch-negative recipients. Graft survival was significantly lower in crossmatch-positive recipients at 1 month after transplant (chi-square=10.3, P=0.00133) but not at 3 months or 1 year. Causes of early graft loss were associated with immunological mechanisms, whereas later losses were due to nonimmunological mechanisms. CONCLUSIONS: Early graft loss may be increased in those recipients who are crossmatch positive. However, the logistical problems and consequences associated with allocation probably outweigh the benefits of prospective crossmatching.

Liver transplantation for alcoholic liver disease: evaluation of a selection protocol.

We have used a formal transplant protocol to select patients with alcoholic liver disease (ALD) for transplantation. We retrospectively analyzed all the patients with ALD who were referred specifically for transplantation to our Liver Unit between 1987 and 1994. Patients were selected for liver transplantation if they had end-stage liver disease and had remained abstinent from the time they were medically advised to stop alcohol intake. Of the 180 patients referred for transplantation, 43 (none of whom were transplanted) had case records insufficiently complete for full analysis; this may bias the analysis. Of the remaining 137 patients, 39 were transplanted and 4 were awaiting transplantation at the time of analysis. Of the patients who were not accepted for transplantation, 13 died during the assessment, 7 were considered to be unlikely to survive the procedure, 29 were found to be medically unsuitable, 16 psychologically unsuitable, 7 patients refused the offer of transplantation, and an additional 19 either showed clinical improvement or were considered too well for transplantation. Special investigations, such as brain computerized tomography (CT) scan and echocardiograph, changed the clinical decision to transplant in only a small number of cases (4% and 5%, respectively). Nine of the transplanted patients died and the remaining were followed up for a median of 25 (range, 7-63) months. One year actuarial survival for the transplanted patients was 79%, for those considered too sick was 0%, for medically unsuitable patients was 44%, for psychologically unsuitable patients was 65% and for those considered too well was 94%. Only 5 of the transplanted patients (13%) reverted to drinking. The observed actuarial survival of nontransplanted patients was compared with the expected survival calculated by 'the Beclere model.' The observed actuarial survival in the nontransplanted groups was much better than anticipated from the Beclere model, which therefore, is not applicable to our patients. The proportional hazards regression analysis of our nontransplanted patients identified serum bilirubin, serum albumin, blood urea, ascites, and spontaneous bacterial peritonitis as factors significantly predictive of their probability of survival. Using a model based on these parameters, the expected survival of our transplanted patients was calculated. Although we applied the model to a different population, the observed actuarial survival in the transplanted patients was found to be better than their expected survival (P < or = .001). Our protocol was useful in selecting suitable patients with ALD for liver transplantation, which resulted in significant survival advantage with low recidivism rate.