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Hereditary haemorrhagic telangiectasia is a genetic condition of abnormal blood vessel formation resulting from an imbalance of pro- and anti-angiogenic products of the transforming growth factor β/bone morphogenetic protein signalling pathway which contributes to vascular remodelling and maintenance. Hepatic vascular malformations are common although less frequently symptomatic, but may result in high-output cardiac failure, portal hypertension and biliary ischaemia. Whilst the understanding of the genetic and cell signalling pathways that are the hallmark of hereditary haemorrhagic telangiectasia have been clarified, there remain challenges in therapy for these patients. Only patients with symptomatic hepatic vascular malformations require treatment, with most (63%) responding to first-line medical therapy. For non-responders, bevacizumab is effective in reducing cardiac output in those with heart failure secondary to hepatic vascular malformations as well as other manifestations of the disease. Although liver transplantation is the only curative option, optimal timing is critical. Novel anti-angiogenetic drugs and those that target aberrant cell signalling pathway are being explored., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: There is controversy regarding the optimal calcineurin inhibitor type after liver transplant(ation) (LT) for primary sclerosing cholangitis (PSC). We compared tacrolimus with cyclosporine in a propensity score-matched intention-to-treat analysis based on registries representing nearly all LTs in Europe and the US., Methods: From the European Liver Transplant Registry (ELTR) and Scientific Registry of Transplant Recipients (SRTR), we included adult patients with PSC undergoing a primary LT between 2000-2020. Patients initially treated with cyclosporine were propensity score-matched 1:3 with those initially treated with tacrolimus. The primary outcomes were patient and graft survival rates., Results: The propensity score-matched sample comprised 399 cyclosporine-treated and 1,197 tacrolimus-treated patients with PSC. During a median follow-up of 7.4 years (IQR 2.3-12.8, 12,579.2 person-years), there were 480 deaths and 231 re-LTs. The initial tacrolimus treatment was superior to cyclosporine in terms of patient and graft survival, with 10-year patient survival estimates of 72.8% for tacrolimus and 65.2% for cyclosporine (p <0.001) and 10-year graft survival estimates of 62.4% and 53.8% (p <0.001), respectively. These findings were consistent in the subgroups according to age, sex, registry (ELTR vs. SRTR), time period of LT, MELD score, and diabetes status. The acute rejection rates were similar between groups. In the multivariable Cox regression analysis, tacrolimus (hazard ratio 0.72, p <0.001) and mycophenolate use (hazard ratio 0.82, p = 0.03) were associated with a reduced risk of graft loss or death, whereas steroid use was not significant., Conclusions: Tacrolimus is associated with better patient and graft survival rates than cyclosporine and should be the standard calcineurin inhibitor used after LT for patients with PSC., Impact and Implications: The optimal calcineurin inhibitor to use after liver transplantation in patients with primary sclerosing cholangitis has yet to be firmly established. Since randomized trials with long follow-up are unlikely to be performed, multicontinental long-term registry data are essential in informing clinical practices. Our study supports the practice of using tacrolimus instead of cyclosporine in the initial immunosuppressive regimen after liver transplantation for patients with primary sclerosing cholangitis. The retrospective registry-based design is a limitation., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The Risk Estimation of Tumor Recurrence After Transplant (RETREAT) score as a prognostic index for recurrence has been reported previously and has not been validated outside the USA. Our study has validated the score in a single center UK cohort of patients being transplanted for HCC., Methods: LT for HCC between 2008 and 2018 at our center were analyzed. Recurrence-free survival (RFS) was compared by the RETREAT score and validated using Net Reclassification Improvement (NRI) by comparing it to Milan criteria., Results: 346 adult HCC patients were transplanted of whom 313 were included. 28 (8.9%) had a recurrence. Summation of largest diameter and total number of viable tumors (HR = 1.19, p < 0.001), micro-/macro-vascular invasion (HR = 3.74, p = 0.002) and AFP>20 ng/ml (HR = 3.03, p = 0.005) were associated with recurrence on multivariate analysis. RFS decreased with increasing RETREAT score (log-rank p = 0.016). RETREAT performed better than Milan with significant NRI at 1- and 2-years post-transplant (0.43 (p = 0.004) and 0.38 (p = 0.03) respectively)., Conclusion: LT outcomes using the revised UK criteria are equivalent to Milan criteria. Further, RETREAT score was validated as a prognostic index for the first time in a UK cohort and may assist risk stratification, selection for adjuvant therapies and guide surveillance., (Crown Copyright © 2021. Published by Elsevier Ltd. All rights reserved.)

Knowledge of living donor liver transplantation (LDLT) for autoimmune liver diseases (AILDs) is scarce. This study analyzed survival in LDLT recipients registered in the European Liver Transplant Registry with autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis (PSC) and the non-autoimmune disorder alcohol-related cirrhosis. In total, 29 902 individuals enrolled between 1998 and 2017 were analyzed, including 1003 with LDLT. Survival from >90 days after LDLT for AILDs in adults was 85.5%, 74.2%, and 58.0% after 5, 10, and 15 years. Adjusted for recipient age, sex, and liver transplantation era, adult PSC patients receiving LDLT showed increased mortality compared to donation after brain death (DBD) (hazard ratio [HR] = 1.95, 95% confidence interval [CI] = 1.36-2.80, p < .001). Pediatric PSC patients showed also increased mortality >90 days after LDLT compared to DBD (HR = 3.00, 95% CI 1.04-8.70, p = .043). Multivariate analysis identified several risk factors for death in adult PSC patients receiving LDLT including a male donor (HR = 2.49, p = .025). Adult PSC patients with LDLT versus DBD conferred increased mortality from disease recurrence (subdistribution hazard ratio [subHR] = 5.36, p = .001) and biliary complications (subHR = 4.40, p = .006) in multivariate analysis. While long-term outcome following LDLT for AILD is generally favorable, PSC patients with LDLT compared to DBD might be at increased risk of death., (© 2021 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: The influence of sex on primary sclerosing cholangitis (PSC), pre- and postliver transplantation (LT) is unclear. Aims are to assess whether there have been changes in incidence, profile, and outcome in LT-PSC patients in Europe with specific emphasis on sex., Methods: Analysis of the European Liver Transplant Registry database (PSC patients registered before 2018), including baseline demographics, donor, biochemical, and clinical data at LT, immunosuppression, and outcome., Results: European Liver Transplant Registry analysis (n = 6463, 32% female individuals) demonstrated an increasing number by cohort (1980-1989, n = 159; 1990-1999, n = 1282; 2000-2009, n = 2316; 2010-2017, n = 2549) representing on average 4% of all transplant indications. This increase was more pronounced in women (from 1.8% in the first cohort to 4.3% in the last cohort). Graft survival rate at 1, 5, 10, 15, 20, and 30 y was 83.6%, 70.8%, 57.7%, 44.9%, 30.8%, and 11.6%, respectively. Variables independently associated with worse survival were male sex, donor and recipient age, cholangiocarcinoma at LT, nondonation after brain death donor, and reduced size of the graft. These findings were confirmed using a more recent LT population closer to the current standard of care (LT after the y 2000)., Conclusions: An increasing number of PSC patients, particularly women, are being transplanted in European countries with better graft outcomes in female recipients. Other variables impacting outcome include donor and recipient age, cholangiocarcinoma, nondonation after brain death donor, and reduced graft size., Competing Interests: M.A.H. is a consultant to Roche and Novartis. M.B. has received grant funding via her institution from Gilead, is a consultant to Intercept, and has received honoraria for lectures sponsored by Abbvie, Astellas, Novartis, and Intercept. The other authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background & Aims: Chronic liver disease and liver transplantation (LT) can delay both timing and ability of women to conceive. With increased awareness and availability of in vitro fertilisation (IVF), the need for accurate counselling is paramount. To date, minimal data exist on outcomes of IVF in patients with chronic liver disease, cirrhosis, or post-LT. We report the largest experience of IVF in women with liver-related subfertility (LRSF)., Methods: A retrospective analysis was performed on 42 women with LRSF who had undergone 57 IVF cycles between 1990 and 2019., Results: Forty-two women with LRSF received IVF; 9 cycles in 6 women with cirrhosis, 14 cycles in 11 women post-LT, and 34 cycles in 25 women without cirrhosis. The main aetiologies of liver disease included HBV, HCV, and autoimmune hepatitis (AIH). Of 57 IVF cycles evaluated, 43 (75%) resulted in successful implantation. Eight (2 post-LT, 3 with cirrhosis, 4 without cirrhosis) resulted in miscarriage. The live birth rate (LBR) was 74% (32/43). Two of 9 (22%) patients with cirrhosis, 4/14 (29%) patients who were post-LT, and 6/34 (18%) patients without cirrhosis had unsuccessful IVF attempts. Nine of 57 (16%) IVF cycles resulted in new liver enzyme derangement during therapy, which improved after treatment completion. Six pregnancies (2 in patients who were post-LT, 4 without cirrhosis) were complicated by obstetric cholestasis (OC). Ovarian hyperstimulation syndrome (OHSS) was rare (n = 3, 7%). One patient with AIH-related cirrhosis decompensated after initiating IVF, warranting discontinuation of therapy. There were no maternal deaths. Three women developed a hypertensive disorder of pregnancy. Half the pregnancies resulted in premature deliveries (range 27-36 weeks)., Conclusions: In selected cases, IVF in women with LRSF can be successful. However, patients should be counselled on the potential increased risks of OHSS, OC, and prematurity., Lay Summary: Women with liver disease or those who have had a liver transplant can experience difficulties getting pregnant. In this study, we look at whether alternative approaches to achieve pregnancy are harmful in these women. Overall, there were no significant issues with the use of in vitro fertilisation in women with liver disease, but they need to be aware of potential risks, such as early delivery of the baby., Competing Interests: Conflicts of interest The authors have no conflicts of interest to declare. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021. Published by Elsevier B.V.)

Background and Aims: Identifying how the prognostic impact of performance status (PS) differs according to indication, era, and time period ("epoch") after liver transplantation (LT) could have implications for selection and treatment of patients on the waitlist. We used national data from the United Kingdom and Ireland to assess impact of PS on mortality separately for HCC and non-HCC recipients., Approach and Results: We assessed pre-LT PS using the 5-point modified Eastern Cooperative Oncology Group scale and used Cox regression methods to estimate hazard ratios (HRs) that compared posttransplantation mortality in different epochs of follow-up (0-90 days and 90 days to 1 year) and in different eras of transplantation (1995-2005 and 2006-2016). 2107 HCC and 10,693 non-HCC patients were included. One-year survival decreased with worsening PS in non-HCC recipients where 1-year survival was 91.9% (95% confidence interval [CI], 88.3-94.4) in those able to carry out normal activity (PS1) compared to 78.7% (95% CI, 76.7-80.5) in those completely reliant on care (PS5). For HCC patients, these estimates were 89.9% (95% CI, 85.4-93.2) and 83.1% (95% CI, 61.0-93.3), respectively. Reduction in survival in non-HCC patients with poorer PS was in the first 90 days after transplant, with no major effect observed between 90 days and 1 year. Adjustment for donor and recipient characteristics did not change the findings. Comparing era, post-LT mortality improved for HCC (adjusted HR, 0.55; 95% CI, 0.40-0.74) and non-HCC recipients (0.48; 95% CI, 0.42-0.55), but this did not differ according to PS score (P = 0.39 and 0.61, respectively)., Conclusions: Impact on mortality of the recipient's pretransplant PS is principally limited to the first 3 months after LT. Over time, mortality has improved for both HCC and non-HCC recipients and across the full range of PS., (© 2020 by the American Association for the Study of Liver Diseases.)

Pregnancy after liver transplantation (LT) is increasingly common and is a frequent scenario that transplant physicians, obstetricians, and midwives encounter. This review summarizes the key issues surrounding preconception, pregnancy-related outcomes, immunosuppression, and breastfeeding in female LT recipients. Prepregnancy counseling in these patients should include recommendations to delay conception for at least 1-2 years after LT and discussions about effective methods of contraception. Female LT recipients are generally recommended to continue immunosuppression during pregnancy to prevent allograft rejection; however, individual regimens may need to be altered. Although pregnancy outcomes are overall favorable, there is an increased risk of maternal and fetal complications. Pregnancy in this cohort remains high risk and should be managed vigilantly in a multidisciplinary setting. We aim to review the available evidence from national registries, population-based studies, and case series and to provide recommendations for attending clinicians., (Copyright © 2019 by the American Association for the Study of Liver Diseases.)

Introduction & Aims: Small studies have found that black patients with autoimmune hepatitis (AIH) present with more aggressive disease. We aimed to characterize the presentation and outcome in black and white patients with AIH., Methods: We performed a retrospective study, collecting information from databases of patients with AIH attending the Institute of Liver studies at King's College Hospital, London (1971-October 2015, the Royal Free Hospital, London (1982 through December 2016) and the multicenter Dutch Autoimmune Hepatitis Study Group cohort (2006-August 2016). We identified 88 black patients with AIH and we compared their clinical characteristics and outcomes to 897 white patients with AIH., Results: Black patients presented at a younger age (median 38 years vs 45 years) (P = .007), had higher IgG levels (mean 31.0 mg/dL vs 27.5 mg/dL) (P = .04), but there were no significant differences between groups in auto-antibody profiles, International AIH Group scores, or sex distribution of disease. A higher proportion of black patients had systemic lupus erythematosus (10%) than white patients (2%) (P ≤ .001). There was no significant difference in proportions of patients with a response to standard therapy (86% for black patients vs 91% for white patients; P = .20) or in rate of relapse (57% vs 50%; P = .3). Despite this, black patients had an increased risk of liver transplantation and liver-related death (hazard ratio 2.4, 95% confidence interval, 1.4-4.0; P < .001). Overall mortality was similar between the two groups., Conclusion: In a comparison of black and white patients with AIH in Europe, we found that black patients present at a younger age, have higher levels of IgG levels, and a greater proportion have SLE. We also found black patients to have a greater risk of liver transplantation and liver-related mortality, indicating more aggressive disease., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Acute severe presentations of autoimmune hepatitis (AIH) represent a challenge for the transplant community. As a disease, it is poorly characterized, and there is a weak evidence base to guide diagnosis and treatment. Early identification of acute severe AIH is key because it determines the initiation of corticosteroids, which can be lifesaving. However, their use in this setting remains controversial. The Model for End-Stage Liver Disease score, severity of coagulopathy, and grade of encephalopathy may be predictors of outcome with corticosteroid therapy. The optimal timing of liver transplantation (LT) can be difficult to determine and, as such, the decision to proceed to transplantation should not be delayed by protracted courses of corticosteroids. The aim of this review is to better characterize this subset of patients; to differentiate them clinically, serologically, and histologically from chronic AIH and other causes of acute liver failure; and to present the role, predictors, and optimal timings of corticosteroid therapy and LT. Although this review is specific to adults, many principles hold true for the pediatric population., (Copyright © 2019 by the American Association for the Study of Liver Diseases.)

Autoimmune liver diseases (AILDs) can recur following liver transplantation (LT) despite immunosuppressive therapy, with implications for graft survival. Although the evidence is not robust, disease recurrence seems to occur in the presence of less intense and/or steroid-free immunosuppression (IS) in particular in the case of autoimmune hepatitis (AIH). The main risk factor for AIH recurrence is the severity of disease activity in the explant and potential donor/recipient human leukocyte antigen D-related 3 (DR3) mismatch. The treatment for AIH recurrence includes reintroduction or increase in the dose of steroids with or without the addition of azathioprine. T cell-mediated rejection episodes are also more common in AILD. Steroid withdrawal is the common practice in LT for non-AILD, eliminating the risks associated with longterm exposure to steroids. In AILD, maintenance of steroids at a low dose in the long term may reduce the risk of disease recurrence and rejection. This strategy is safe when there is vigilance for steroid-related adverse effects. Alternatively, identifying patients who are at the greatest risk for disease recurrence and who would benefit from intensified IS might be an option., (© 2018 The Authors. Liver Transplantation published by Wiley Periodicals, Inc. on behalf of American Association for the Study of Liver Diseases.)

Liver transplantation (LT) is a successful treatment for both acute liver failure and end-stage liver disease. The number of women of reproductive age undergoing LT is increasing. Pregnancy outcomes are favorable, but there is still a lack of prognostic markers. We aimed to identify factors predictive of adverse pregnancy outcomes in LT recipients. An analysis of all pregnancies occurring in LT recipients from 1989 to 2016 at King's College Hospital was performed. Clinical data of 162 conceptions in 93 women were reviewed. Descriptive and regression analyses were done to examine associations between laboratory markers and hepatological scores with pregnancy outcomes of live birth and preterm birth. Median age at LT was 23 years (range, 1-41 years), with a median age at conception of 30 years (range, 18-47 years). The live birth rate was 75% (n = 121). Of live births, 35% (n = 39/110 available) were delivered preterm. Preconception creatinine levels were higher in patients who had a preterm birth (85 versus 74 μmol/L; P = 0.008), with a preconception estimated glomerular filtration rate (eGFR) <90 mL/minute significantly associated with preterm delivery (P = 0.04). Progressive decline in eGFR predicted outcome, with gestational length declining with increasing chronic kidney disease (CKD) stage: CKD 0-1 = 39 weeks (median), CKD 2 = 37 weeks, and CKD 3 = 35 weeks. The risk of preterm birth was greatest in women with an eGFR <60 mL/minute (P = 0.004). Moreover, hypertension-related complications during pregnancy, such as gestational hypertension, preeclampsia, or eclampsia, were also associated with prematurity (P = 0.01). Women taking steroid-based immunosuppression had an increased risk of infection during pregnancy or postpartum (15% versus 4%; P = 0.02). In conclusion, although the majority of women have a successful pregnancy outcome after LT, preconception renal function predicts pregnancy outcome and steroids increase risk of infection during pregnancy or postpartum. Liver Transplantation 24 606-615 2018 AASLD., (© 2018 by the American Association for the Study of Liver Diseases.)

Current diagnostic criteria for primary nonfunction (PNF) of liver grafts are based on clinical experience rather than statistical methods. A retrospective, single-center study was conducted of all adults (n = 1286) who underwent primary liver transplant (LT) 2000-2008 in our center. Laboratory variables during the first post LT week were analyzed. Forty-two patients (3.7%) had 2-week graft failure. Transplant albumin, day-1 aspartate aminotransferase (AST), day-1 lactate, day-3 bilirubin, day-3 international normalized ratio (INR), and day-7 AST were independently associated with PNF on multivariate logistic regression. PNF score =(0.000280*D1AST)+ (0.361*D1 Lactate)+(0.00884*D3 Bilirubin)+(0.940*D3 INR)+(0.00153*D7 AST)-(0.0972*TxAlbumin)-4.5503. Receiver operating curve analysis showed the model area under receiver operating curve (AUROC) of 0.912 (0.889-0.932) was superior to the current United Kingdom (UK) PNF criteria of 0.669 (0.634-0.704, p < 0.0001). When applied to a validation cohort (n = 386, 34.4% patients), the model had AUROC of 0.831 (0.789-0.867) compared to the UK early graft dysfunction criteria of 0.674 (0.624-0.721). The new model performed well after exclusion of patients with marginal grafts and when modified to include variables from the first three post-LT days only (AUROC of 0.818, 0.776-0.856, p = 0.001). This model is superior to the current UK PNF criteria and is based on statistical methods. The model is also applicable to recipients of all types of grafts (marginal and nonmarginal)., (© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Improvements in the management of patients undergoing liver transplantation (LT) have resulted in a significant increase in survival in recent years. Cardiac disease is now the leading cause of early mortality, and the stress of major surgery, hemodynamic shifts, and the possibilities of hemorrhage or reperfusion syndrome require the recipient to have good baseline cardiac function. The prevalence of coronary artery disease (CAD) is increasing in LT candidates, especially in those with nonalcoholic fatty liver disease. In assessing LT recipients, we suggest a management paradigm of "quadruple assessment" to include (1) history, examination, and electrocardiogram; (2) transthoracic echocardiogram; (3) functional testing; and (4) where appropriate, direct assessment of CAD. The added value of functional testing, such as cardiopulmonary exercise testing, has been shown to be able to predict posttransplant complications independently of the presence of CV disease. This approach gives the assessment team the greatest chance of detecting and preventing complications related to CAD. Liver Transplantation 23 386-395 2017 AASLD., (© 2016 by the American Association for the Study of Liver Diseases.)

Objective: Natural killer (NK) cells are important mediators of liver inflammation in chronic liver disease. The aim of this study was to investigate why liver transplants (LTs) are not rejected by NK cells in the absence of human leukocyte antigen (HLA) matching, and to identify a tolerogenic NK cell phenotype., Design: Phenotypic and functional analyses on NK cells from 54 LT recipients were performed, and comparisons made with healthy controls. Further investigation was performed using gene expression analysis and donor:recipient HLA typing., Results: NK cells from non-HCV LT recipients were hypofunctional, with reduced expression of NKp46 (p<0.05) and NKp30 (p<0.001), reduced cytotoxicity (p<0.001) and interferon (IFN)-γ secretion (p<0.025). There was no segregation of this effect with HLA-C, and these functional changes were not observed in individuals with HCV. Microarray and RT-qPCR analysis demonstrated downregulation of STAT4 in NK cells from LT recipients (p<0.0001). Changes in the expression levels of the transcription factors Helios (p=0.06) and Hobit (p=0.07), which control NKp46 and IFNγ expression, respectively, were also detected. Hypofunctionality of NK cells was associated with impaired STAT4 phosphorylation and downregulation of the STAT4 target microRNA-155. Conversely in HCV-LT NK cell tolerance was reversed, consistent with the more aggressive outcome of LT for HCV., Conclusions: LT is associated with transcriptional and functional changes in NK cells, resulting in reduced activation. NK cell tolerance occurs upstream of major histocompatibility complex (MHC) class I mediated education, and is associated with deficient STAT4 phosphorylation. STAT4 therefore represents a potential therapeutic target to induce NK cell tolerance in liver disease., Competing Interests: Conflicts of Interest: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Young people (YP) with chronic illness have higher rates of mental health problems than the general population, with psychosocial complexity associated with nonadherence and poorer health outcomes. This study aimed to describe the prevalence of anxiety and depression in YP after liver transplantation, with autoimmune liver disease and other chronic liver diseases, identify the factors YP attribute their distress to and the relationship between anxiety/depression, and describe YP's beliefs about their illness and treatment. An electronically administered questionnaire battery was given routinely to YP attending an outpatient liver transition clinic; 187 YP participated, of which 17.7% screened positive for anxiety or depression. There were no significant differences between disease groups. This is significantly higher than the prevalence of common mental health problems in the general adolescent population. Patients most frequently attributed their distress to fatigue, sleep difficulties, financial concerns, problems at work/school, worry, and low self-esteem. Higher levels of depression and anxiety were significantly associated with specific illness and treatment beliefs but not with perceived understanding of illness or treatment control. In conclusion, the increased prevalence of mental health problems in YP and the intertwined nature of these with their physical health outcomes provide evidence that holistic care should be delivered as standard for this age group. Liver Transplantation 22 1544-1553 2016 AASLD., (© 2016 by the American Association for the Study of Liver Diseases.)

Reports of pregnancy in liver transplantation (LT) patients have largely favorable outcomes. Concerns remain with regards to maternal and graft risk, optimal immunosuppression (IS), and fetal outcomes. We review all post-LT pregnancies at our center with regard to the outcomes and safety for the patient, graft, and fetus. A total of 117 conceptions occurred in 79 patients. Median age at conception was 29 years. Maternal complications included graft loss (2%), acute cellular rejection (ACR; 15%), pre-eclampsia/eclampsia (15%), gestational diabetes (7%), and bacterial sepsis (5%). ACR was significantly more common in those women who conceived within 12 months of LT (P = 0.001). The live birth rate was 73%. Prematurity occurred in 26 (31%) neonates, and 24 (29%) neonates were of low or very low birth weight. IS choice (cyclosporine versus tacrolimus) had no significant effect on pregnancy outcomes and complications. No congenital abnormalities occurred, and only 1 child born at 24 weeks had delayed developmental milestones. In conclusion, pregnancy following LT has a favorable outcome in the majority, but severe maternal risks remain. Patients should be counseled with regard to the above information so informed decisions can be made, and pregnancy must be considered high risk with regular monitoring by transplant clinicians and specialist obstetricians., (© 2015 American Association for the Study of Liver Diseases.)

Purpose of Review: Acute liver failure (ALF) is a rare but life-threatening systemic disorder. Survival rates with or without emergency liver transplantation (ELT) are increasing. The benefit of ELT in some cases has been questioned and the potential for survival with medical management alone is changing our approach to the management of this disease., Recent Findings: Survival rates for all causes of ALF are increasing because of improvements in the care of the critically ill patient. A multifactorial approach involving support of respiratory, circulatory and renal function together with measures to avoid intracranial hypertension, metabolic disequilibrium and sepsis are required. For those who do not respond to these measures or specific antidotes, the selection methods for those likely to benefit from transplantation remain imperfect and novel methods based on the prediction of hepatic regeneration are required. For patients with ALF secondary to acetaminophen overdose, some experts believe a randomized controlled trial is required to find those most likely to benefit from ELT., Summary: ALF remains a life-threatening condition with a high mortality rate requiring prompt support of multiorgan failure. Historical listing criteria for ELT are being questioned and improvement in medical management offers the option of continued improvements in transplant-free survival.

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., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Introduction: Sun exposure is a major risk factor for the development of skin cancer. This is particularly relevant in immunosuppressed liver-transplant recipients (LTRs). Preventative strategies may help minimize the skin-cancer risk in this patient group., Methods: We assessed 670 patients in our post-transplant clinic, using questionnaires. Patient data were collected, and we assessed whether patients had received education (such as formal talks or information from transplant coordinators or from hepatologists) on skin, sun exposure and skin cancer. In a subset of 280 of the LTRs who responded, we recorded their recall of sun-protection advice and assessed the level of patient adherence to such advice., Results: The response rate was 57.5% (349/607), with a mean responder age of 51.1 years (range 19-84) and an average post-transplant time of 7.1 years (range 0-27). In the recall assessment, 37.2% reported that they were given advice about their skin, while 18.1% were seen by a dermatologist, and education on sun exposure and the risks of skin cancer was given to 65.6% and 47.9%, respectively. Over three-quarters (78%; 185/280) of the patients used mechanical sun protection (i.e. hats/clothing), while 66% reported using sunscreen; 31.8% of these used a sunscreen of the recommended sun protection factor (SPF) of > 30. Twelve patients had developed squamous cell carcinoma after a mean of 10.9 years (1-23) post-transplant; half of these had used either no sunscreen or one with an SPF of < 15., Conclusions: Despite the fact that LTRs are given information on sun-exposure and SC before and after transplantation, recall of such advice and use of sun-protection methods was only moderate, indicating that regular reinforcement of SC education is needed., (© 2013 British Association of Dermatologists.)

Recent data suggest an association of serum ferritin (SF) with waiting list (WL) and postliver transplant (LT) outcomes. To assess the predictive capacity of SF on pre- and post-LT outcomes, and to identify whether recipient or donor liver siderosis is associated with post-LT survival; a retrospective analysis of 1079 patients assessed for first LT, 2000-2007 was performed. Iron deposition in the liver tissue was assessed using a semi-quantitative grading system. Median age was 54 (18-82) years and 67% were male. Seventeen per cent had hepatocellular carcinoma (HCC). Median Model for End-stage Liver Disease MELD score was 14 (6-40), ferritin was 174 μg/l (4-4597) with 36.5% had a SF ≥ μg/l. Age (OR = 1.028) and MELD score (OR = 1.158) were independently associated with WL mortality (P < 0.001), whilst SF was not (P = NS). Age (OR = 1.018), HCC (OR = 1.542) and cold ischemia time (CIT) ≥ 10 h (OR = 1.418) were independently associated with post-LT survival (P < 0.05). Explant siderosis grade <2 was seen in 376 (71.7%) patients. Patients with explant siderosis grade ≥ 2 had inferior 12-month post-LT survival (P = 0.030). Presence of graft siderosis (15.8% of patients) was not associated with survival. In conclusion, we found a limited role for SF as a prognostic indicator for pre- or post-transplant survival., (© 2013 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)

Background & Aims: Liver transplantation improves survival in end-stage primary biliary cirrhosis (PBC), but the benefit for systemic symptoms including fatigue is less clear. The aim of this study was to utilise the comprehensive UK-PBC Research Cohort, including 380 post-transplant patients and 2300 non-transplanted patients, to answer key questions regarding transplantation for PBC., Methods: Cross-sectional study of post-transplant PBC patients and case-matched non-transplanted patients. Detailed clinical information was collected, together with patient systemic symptom impact data using validated assessment tools., Results: Over 25% of patients in the transplant cohort were grafted within 2 years of PBC diagnosis suggesting advanced disease at presentation. Transplanted patients were significantly younger at presentation than non-transplanted (mean 7 years) and >35% of all patients in the UK-PBC cohort who presented under 50 years had already undergone liver transplantation at the study censor point (>50% were treatment failures (post-transplant or unresponsive to UDCA)). Systemic symptom severity (fatigue and cognitive symptoms) was identical in female post-transplant patients and matched non-transplanted controls and unrelated to disease recurrence or immunosuppression type. In males, symptoms were worse in transplanted than in non-transplanted patients., Conclusions: Age at presentation is a major risk factor for progression to transplant (as well as UDCA non-response) in PBC. Although both confirmatory longitudinal studies, and studies utilising objective as well as subjective measures of function, are needed if we are to address the question definitively, we found no evidence of improved systemic symptoms after liver transplantation in PBC and patients should be advised accordingly. Consideration needs to be given to enhancing rehabilitation approaches to improve function and life quality after liver transplant for PBC., (Copyright © 2013. Published by Elsevier B.V.)

Background: An association between primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) is well recognized. However, the disease course of IBD following liver transplantation (LT) for PSC remains ill-defined., Aims and Methods: We aimed to assess the impact of IBD in patients that had undergone LT for PSC to help identify risk factors for flare and to assess the impact of IBD on graft survival., Results: 110 patients underwent LT for PSC (Oct 1990-Aug 2009) at King's College Hospital. 74 (67%) patients had concurrent IBD and 36 had PSC alone prior to transplant. 39 patients developed IBD (flare of IBD and de-novo) post transplant. Cumulative risk for IBD at 1-, 2-, 5- and 10-years was 16%, 24%, 38% and 72% respectively. Flare of IBD occurred in 33 patients with a mean time to flare of 30 ± 28 months. De-novo IBD occurred in 6 patients (all UC). Mean time to diagnosis was 29 ± 25 months. Multivariate cox-regression analysis identified active IBD at time of LT as a significant predictor of graft failure post LT (HR 10, CI 3-39, P = 0.001) and smoking at time of transplantation and subsequent cessation predictive of recurrent IBD post transplantation (HR 17, 2-180, P = 0.02)., Conclusion: In conclusion, smoking at time of LT was predictive of flare of IBD and active IBD at time of transplantation had a significant effect on graft survival. Medical therapy needs to be maximised in the pre-LT period. Patients with poorly controlled IBD refractory to medical therapy should be considered for colectomy at time of transplantation., (© 2011 John Wiley & Sons A/S.)

Latent myeloproliferative disorders (MPDs) can be identified by Janus kinase 2 (JAK2) mutations in patients with idiopathic Budd-Chiari syndrome (BCS). The incidence and clinical outcomes of JAK2 mutations, novel ten-eleven translocation 2 (TET2) mutations, and the 46/1 haplotype in BCS are unknown for liver transplantation (LT). We undertook molecular studies of 66 patients presenting with BCS and correlated the results with the clinical outcomes. An overt MPD was present in 20% of the cases, and a latent MPD confirmed by the presence of a JAK2 mutation was detected in 45%. Testing for a TET2 mutation identified MPDs at the molecular level in another 7% of the subset of patients with BCS who were evaluated. The 46/1 haplotype frequency was significantly greater in BCS patients versus the general population (P < 0.001). The presence of JAK2 and TET2 mutations had no impact on 1-year survival. Thirty-six patients underwent LT, and 12 developed liver-related thrombotic complications (33%). Ten of these 12 patients required retransplantation. Retransplantation was more likely in those patients who developed liver-related thrombotic complications (P < 0.001). A JAK2 mutation was highly associated with the development of thrombotic complications after LT (P = 0.005). In conclusion, the presence of JAK2V617F predicts hepatic and extrahepatic thrombotic complications after LT. Testing for TET2 mutations can identify another 7% of idiopathic BCS patients with molecular MPDs., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Background: Hepatocellular carcinoma (HCC) is a major cause of morbidity and mortality worldwide. Liver transplantation offers a potential cure for this otherwise devastating disease. The selection of the most appropriate candidates is paramount in an era of graft shortage., Aim: To review systematically the role of liver transplantation in the management of HCC in current clinical practice., Methods: An electronic literature search using PUBMED (1980-2010) was performed. Search terms included HCC, hepatoma, liver cancer, and liver transplantation., Results: Liver transplantation is a highly successful treatment for HCC, in patients within Milan criteria (MC), defined as a solitary tumour ≤50 mm in diameter or ≤3 tumours ≤30 mm in diameter in the absence of extra-hepatic or vascular spread. Other eligibility criteria for liver transplantation are also used in clinical practice, such as the University of California, San Francisco criteria, with outcomes comparable to MC. Loco-regional therapies have a role in the bridging treatment of HCC by minimising wait-list drop-out secondary to tumour progression. Beyond MC, encouraging results have been demonstrated for patients with down-staged tumours. Post-liver transplantation, there is no evidence to support a specific immunosuppressive regimen. In the context of an insufficient cadaveric donor pool to meet demand, the role of adult living donation may be increasingly important., Conclusions: Liver transplantation offers a curative therapy for selected patients with HCC. The optimisation of eligibility criteria is paramount to ensure that maximum benefit is accrued. Although wait-list therapies have been incorporated into clinical practice, additional high quality data are required to support this strategy., (© 2012 Blackwell Publishing Ltd.)

Liver transplantation (LT) for human immunodeficiency virus (HIV)-positive recipients with end-stage liver disease has become an accepted practice. However, because these patients are increasingly being recognized as prothrombotic, we reviewed their posttransplant thrombotic complications. Because morphological changes might be responsible in part for this prothrombotic state, we also conducted a histopathological review of explants from HIV-positive patients. Between 1990 and 2010, 24 of 3502 recipients (including 23 adults) were HIV-positive at LT. These patients and their postoperative courses were reviewed with a particular focus on vascular complications, risk factors, and outcomes. Another patient in whom HIV was detected 12 years after LT was also examined. Among the 24 HIV-positive LT recipients (17 males and 22 whole liver grafts; median age = 40 years), 5 developed arterial complications [including 3 cases of hepatic artery thrombosis (HAT), 1 case of generalized arteriopathy (on angiography), and 1 case of endoarteritis (on histological analysis)]. Multiple arterial anastomoses were performed in 8 of the 24 recipients, and HAT occurred twice within this anastomosis group. The outcomes of the 3 patients with HAT included retransplantation, biliary stenting for ischemic cholangiopathy followed by retransplantation, and observation only. In addition, 5 separate venous thrombotic events were detected in the 24 recipients during this period. Moreover, the delayed-HIV recipient developed delayed HAT and subsequently ischemic cholangiopathy and was being assessed for retransplantation at the time of this writing. In conclusion, the prothrombotic state associated with combined HIV and liver disease is a cause of morbidity after LT: 8 of the 24 recipients (33%) in this series suffered vascular thrombotic complications. There is a potential increase in the risk of HAT: the rate for the HIV-positive cohort was higher than the rate for historical HIV-negative controls [12% versus 3.2%, P = 0.016 (Fisher's exact test)]. The minimization of complex arterial reconstruction, coagulopathy screening, and risk-adapted antithrombotic chemoprophylaxis appear to be reasonable precautions., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Hepatitis C virus (HCV) infection has become the most common indication for liver transplantation in the United States and Europe. Recurrence of HCV is universal in all liver graft recipients, but the natural history of the disease is variable with some patients displaying slowly progressive liver injury, while approximately 30% become cirrhotic within five yr of surgery. Currently, liver biopsy is the reference standard to assess liver injury in the post-transplant setting. But biopsy is associated with complications such as bleeding and pain, as well as the risk of sampling error and discordance in reporting between histopathologists. Thus, as in the pre-transplant setting, there is increasing attention being drawn to the use of non-invasive tests of liver fibrosis. This review examines the role of non-invasive assessment of hepatic fibrosis in the post-transplant setting including simple tests such as aspartate aminotransferase-to-platelet ratio index, the Benlloch formula, London Transplant Centre score, and finally transient elastography. The authors assess the respective advantages and disadvantages of the tests and consider how non-invasive tests of liver fibrosis can be utilized in the future management of post-transplant HCV infection., (© 2011 John Wiley & Sons A/S.)

Postoperative acute kidney injury (AKI) increases morbidity and mortality after liver transplantation (LT). Novel methods of assessing AKI including cystatin C (CyC) and neutrophil gelatinase-associated lipocalin (NGAL) have been identified as potential markers of AKI. We compare the ability of standard renal markers (serum creatinine [sCr], estimated glomerular filtration rate [eGFR] and intensive therapy unit organ failure scores with CyC and NGAL to predict AKI within the first 48 hours after LT. 95 patients (median age 50 [interquartile range = 41-59], 60% male) underwent LT (25% with acute liver failure). AKI was defined according to the Acute Kidney Injury Network criteria. Severe AKI was classified as ≥stage 2. NGAL (urine [u] and plasma [p]) and CyC concentrations taken immediately after transplantation on admission to the Liver Intensive Care Unit were compared with standard markers of renal function. Predictive ability was assessed using the area under the curve generated by receiver operator characteristic analysis (AUROC) and logistic regression. Day 0 sCr, uNGAL, pNGAL, CyC, and eGFR predicted AKI as did SOFA (Sequential Organ Failure Assessment) and APACHE II (Acute Physiology and Chronic Health Evaluation II) scores. APACHE II and pNGAL were the most powerful predictors of severe AKI (APACHE II AUROC = 0.87 [0.77-0.97], P < 0.001; pNGAL AUROC = 0.87 [0.77-0.92], P < 0.001). Using multivariate logistic regression, APACHE II (odds ratio 1.64/point [95% confidence interval = 1.22-2.21, P = 0.001] and pNGAL [odds ratio = 1.01/ng/mL [95% confidence interval = 1.00-1.02], P = 0.002) retained independent significance. A "renal risk score" using APACHE II > 13 and pNGAL > 258 ng/mL was calculated with a score of ≥1 having a 100% sensitivity and 76% specificity for severe AKI. In conclusion, a combination of NGAL and APACHE II predicts AKI with high sensitivity and specificity after LT., (© 2010 AASLD.)

Recurrent hepatitis C is a common cause of graft loss in patients undergoing liver transplantation, and serial protocol liver biopsies have been used to identify patients at risk of graft loss from rapid fibrosis progression. The aim of this study was to derive a simple noninvasive index to predict fibrosis in patients with recurrent hepatitis C post-transplant. A retrospective study was performed assessing serial liver biopsies for post-transplant chronic hepatitis C infection. One hundred eighty-five patients were included in the analysis; median age 53 years (interquartile range 48-59) and 140 (76%) were male. Liver histology showed 53 (29%) had Ishak fibrosis stages F0/F1, 31 (17%) had F2, 29 (16%) had F3, 19 (10%) had F4 and 53 (29%) had F5/F6. The London Transplant Centres' (LTC) score was derived combining aspartate aminotransferase (AST IU/L), time from liver transplant (TFLT months), international normalized ratio and platelets. Diagnostic accuracy of the LTC score was assessed using area under receiver-operating characteristic (ROC) curves. The area under the ROC curve for moderate fibrosis (F >or= 2) was 0.78 (95% CI, 0.70-0.86; P < 0.0001), for advanced fibrosis (F4-6) was 0.80 (95% CI, 0.72-0.87; P < 0.0001) and for cirrhosis was 0.80 (95% CI, 0.72-0.88; P < 0.0001). An optimal cut-off value of 6.3 distinguished patients with no or mild fibrosis (F

Organ allocation based on Model for End-Stage Liver Disease (MELD) resulted in decreased waiting list mortality in the United States. However, reports suggest an increase in resource utilization as a consequence of this. The aim of this study is to assess the correlation of MELD at transplant with post-liver transplant (LT) intensive care unit (ICU) costs. We assessed clinical and demographic variables of 402 adult patients who underwent LT at King's College Hospital, London, UK, between January 2000 and December 2003. ICU cost calculations were based on the therapeutic intervention scoring system (TISS). Graft quality was assessed using the donor risk index (DRI). Patients with a MELD score > 24 had significantly longer post-LT ICU stay (P < 0.0001) and total post-LT hospital stay (P = 0.008). In addition, they had significantly increased TISS scores, ICU cost, and need for renal replacement therapy (RRT) (P < 0.001). MELD score (by point) and MELD > 24 was associated with prolonged ICU stay (P = 0.004 and P = 0.005, respectively). On univariate analysis, etiology of alcohol-related liver disease (ALD), repeat LT, Budd-Chiari syndrome, and refractory ascites were associated with prolonged ICU stay. Using multivariate analysis, MELD > 24, refractory ascites, ALD and Budd-Chiari syndrome were associated with prolonged ICU stay. There was no association between using grafts with higher DRI and longer ICU stay, need for RRT, increased cost, or hospital survival on univariate analyses (P = not significant). Use of MELD as a method of organ allocation results in significant increase in ICU cost after LT. Using TISS as surrogate marker for ICU costs reveals that the cost implications are related to the need for RRT and prolonged ICU stay., (2010 AASLD.)

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.

Auxiliary liver transplantation (ALT) permits the serial assessment of regeneration in livers of patients with acute liver failure (ALF). Forty-nine ALF patients [32 adults (median age, 23 years; range, 16-40 years) and 17 children (median age, 12 years; range, 1-15 years)] underwent ALT between 1994 and 2004 at King's College Hospital. Twenty-four patients had seronegative liver failure, 15 had acetaminophen toxicity, 4 had hepatitis B virus (HBV) infection, 3 had drug-induced liver failure, 2 had autoimmune hepatitis, and 1 had mushroom poisoning. Nine patients without post-ALT native liver histology were excluded from review. All acetaminophen-induced, HBV, and drug-related patients had diffuse injury. Twelve seronegative patients and the autoimmune hepatitis patient had a map-like injury. On follow-up, 9 acetaminophen-induced patients, 9 seronegative patients, 2 drug-induced ALF patients, 3 HBV patients, and the autoimmune patient recovered to a near-normal native liver with inconsequential scarring. The hepatocyte proliferative rate in diffuse necrosis was 27.4% (range, 3.1%-69.4%) at hepatectomy and sharply decreased after 8 days post-ALT, being minimal months and years after ALT. In conclusion, in patients undergoing ALT for ALF with a diffuse pattern of liver injury-mainly acetaminophen toxicity-hepatocyte proliferation occurs in the native liver within a few days of transplantation. If the injury is map-like (most cases of seronegative ALF), regeneration seems to involve variable hepatocellular proliferation and potential ductular hepatopoiesis, but sequential assessment is difficult because of sampling variation. The likelihood of histological recovery appears to be minimal in livers with total hepatocyte loss at the time of ALT., ((c) 2008 AASLD.)

Portopulmonary hypertension (PPHTN) represents a constrictive pulmonary vasculopathy in patients with portal hypertension. Liver transplantation (LT) may be curative and is usually restricted to patients with mild-to-moderate disease severity characterized by a mean pulmonary artery pressure (mPAP < 35 mm Hg). Patients with severe disease (mPAP > 50 mm Hg) are usually excluded from transplantation. We describe a patient with severe PPHTN, initiated on sequential and ultimately combination therapy of prostacyclin, sildenafil, and bosentan (PSB) pretransplantation and continued for 2 years posttransplantation. Peak mPAP on PSB therapy was dramatically reduced from 70 mm Hg to 32 mm Hg pretransplantation, and continued therapy facilitated a further fall in mPAP to 28 mm Hg posttransplantation. The pulmonary vascular resistance index fell from 604 to 291 dyne second(-1) cm(-5). The perioperative mPAP rose to 100 mm Hg following an episode of sepsis and fell with optimization of PSB therapy. In conclusion, this is the first reported patient with severe PPHTN using this combination of vasodilator therapy as a bridge to LT and then as maintenance in the posttransplantation phase. This regimen may enable LT in similar patients in the future, without long-term consequences.

With increased demand for liver transplantation (LT), outcomes of older recipients have been subjected to greater scrutiny, as previous studies have demonstrated poorer survival outcomes. Outcomes of 77 patients aged>65 yr (group 1) who underwent transplantation between 1988 and 2003 at King's College Hospital, London, were compared with all recipients aged between 60 and 64 yr (group 2, n=137) and 202 time-matched control patients with chronic liver disease aged between 18-59 yr (group 3). Patient survival at 30-days for groups 1, 2, and 3 were 99%, 94%, and 94%, respectively (P=not significant [NS]). At 1-yr, survival in the 3 groups was 82%, 86%, and 83%, respectively (P=NS), and at 5-yr patient survival was comparable (73%, 80%, and 78%, respectively) (P=NS). Episodes of acute cellular rejection (ACR) were fewer in the older cohorts (43% vs. 45% vs. 61%, P=0.0016), although there was no significant difference identified in the numbers of patients in each group who experienced ACR (P=0.16). A similar but nonsignificant trend was identified for rates of chronic rejection among the groups. In conclusion, these data suggest that survival of patients over 60 and 65 yr undergoing LT is satisfactory, at least in the first 5-yr posttransplantation. In addition, patients over 65 yr experience less rejection, with good graft survival. Thus, LT should not be denied to patients>65 yr on the basis of age alone, once a comprehensive screen for comorbidity has been undertaken., (Copyright (c) 2007 AASLD.)

Allocation of donor livers through the model for end-stage liver disease (MELD) score has resulted in a fall in waiting list deaths in the United States. Change in MELD score (DeltaMELD) whilst awaiting transplant has been suggested as a method of refining organ allocation. Our aims were to analyse the effect of DeltaMELD between listing and transplant, and examine its impact on patient survival, intensive care stay and hospital stay in 402 patients transplanted for chronic liver disease at a single centre. Patients who had a DeltaMELD score of >+1 point were more likely to die in hospital following transplant (P < 0.05) and had a significantly worse 12- and 36-month survival post transplant (P < 0.0001) when compared with patients with DeltaMELD

Despite the recognition of numerous factors for aggressive hepatitis C virus (HCV) recurrence after liver transplantation (LT) our understanding of this phenomenon is incomplete. We tested the hypothesis that diabetes mellitus (DM) was implicated. One hundred sixty-three patients undergoing primary LT for HCV from 1990 to 2004 were evaluated and biopsies were scored according to the modified Ishak score. Severe recurrence of HCV was defined as a fibrosis score > or = 4 within 6 years of LT. Risk factors assessed included recipient, donor and transplant variables. Fifty-four patients (33.1%) had a fibrosis score > or = 4 at the end of the study period. Factors associated with progression to severe fibrosis was donor age (p = 0.008) especially donor age >55 (p = 0.038, HR 2.43), pre-LT DM (p = 0.039, HR 2.68) and DM post-LT (p = 0.004, HR 3.28). The combination of receiving a liver from a donor older than 55 years and having DM post-LT was associated with an 8.38-fold risk of progression to severe fibrosis (p = 0.000124) when compared to patients not diabetic post-LT who received livers from donors aged <55 years. These data indicate that diabetic status is one of the more important variables determining the severity of HCV recurrence and is synergistic with donor age. This observation may provide an additional management opportunity to modify the impact of HCV recurrence.

Infertility is common in women with end-stage liver disease. Successful liver transplant (LT), however, can restore childbearing potential. Controversy exists regarding the most appropriate immunosuppressive regimen and timing of conception following LT. We report the outcomes of a review of all pregnancies occurring following LT at King's College Hospital, London, from 1988 to 2004. Seventy-one pregnancies were recorded in 45 women. Tacrolimus (60%) and cyclosporin A (38%) were the predominant primary immunosuppressive agents used. Median age at conception was 29 years (range, 19-42), with a median time from LT to conception of 40 months (range, 1-111). There were 50 live births, and no maternal or fetal deaths related to pregnancy. There were no graft losses. Median gestation was 37 weeks (range, 24-42) with a median birth weight of 2,690 g (range, 554-4,260). Caesarean section was performed in 40% of pregnancies. Complications included pregnancy-induced hypertension in 20%, preeclampsia in 13%, acute cellular rejection in 17%, and renal impairment in 11%. There was no statistically significant difference in complication rates observed between immunosuppressive groups. Pregnancies occurring within 1-year posttransplant had an increased incidence of prematurity, low birth weight, and acute cellular rejection compared to those occurring later than 1 year. In conclusion, this study confirms that favorable outcomes of pregnancy post-LT can be expected for the majority of patients. However, delaying pregnancy until after 1-year post-LT is advisable, since doing so maybe associated with a lower risk of prematurity., (Copyright 2006 AASLD)

Background: Steroid-resistant rejection (SRR) results in significant morbidity and mortality from the adverse effects of rescue therapy and in graft loss from chronic rejection. In our knowledge, the efficacy and safety of anti-interleukin (IL) 2r antibodies (daclizumab and basiliximab) for the treatment of SRR in adult liver transplantation has not previously been evaluated., Methods: Twenty-five patients received either daclizumab or basiliximab as rescue therapy for SRR. Outcome and biochemical parameters were recorded before and after treatment with an anti-IL-2r antibody., Results: The median time from transplantation to SRR was 25 days. Secondary immunosuppression included mycophenolate mofetil in 18 patients. Twelve patients (48%) had complete resolution of SRR. Aspartate transaminase levels normalized at a median of 37 days (range, 1-168 days). In 13 patients (52%) progressive hepatic dysfunction developed. Four of these patients received another transplant, and 6 patients had chronic rejection. Three patients died with graft failure. Of 16 patients with acute cellular rejection, 12 (75%) had resolution, 2 had chronic rejection, 1 required a repeat transplantation, and 1 died with graft failure. In contrast, all 9 patients with established chronic rejection in their pretreatment biopsy continued to have significant graft dysfunction, with 4 having persistent chronic graft dysfunction, 3 requiring repeat transplantation, and 2 dying with graft failure., Conclusion: Twelve (48%) of 25 patients who received an anti-IL-2r antibody because of SRR were successfully treated. All successfully treated patients had ongoing acute cellular rejection at liver biopsy (75%), whereas patients with histologic evidence of chronic rejection responded poorly.

Background: Chronic hepatitis C virus (HCV) infection is the most common indication for orthotopic liver transplantation (OLT) in the United States. Recent studies from selected centers have suggested that older donor age is associated with worse outcomes after transplantation for HCV., Methods: We analyzed the United Network for Organ Sharing Liver Transplant Registry database from April 1987 to March 2003 to examine predictors of death or retransplantation in patients with HCV. Univariate models for each predictor were evaluated. Factors significant in the univariate model were used to develop a multivariable model., Results: Of 6,956 patients meeting the inclusion/exclusion criteria, 1,527 (22.0%) died or received retransplants during the first year after transplant. Recipients with graft failure were older, had greater serum creatinine levels, and were more likely to require mechanical ventilation and hemodialysis before transplant. Donors of patients with graft failure were older and more likely to have diabetes mellitus. In the multivariable regression model, predictors of graft failure at 1 year were donor age, recipient age, recipient creatinine greater than 2 mg/dL, and the requirement for mechanical ventilation for the recipient., Conclusions: Both older donor age and older recipient age plus markers of severity of disease, including requirement for mechanical ventilation and renal insufficiency, are negatively associated with survival after liver transplantation. These factors should be considered when assessing OLT recipient and donor candidacy in patients with HCV.

In response to the critical organ shortage, transplant professionals have utilized living donors in an attempt to decrease the mortality rate associated with waiting on the liver transplant list. Although the surgical techniques were first utilized clinically 15 years ago, application of LDLT has been somewhat limited by the steep learning curve associated with developing a program. Clinical success with LDLT in children was realized early in the experience and application of the techniques to the adult population has occurred more recently. Although transplant centers embark on LDLT with enthusiasm, the safety of the donor must always be at the forefront of the process. Potential donors must come to the decision to donate without pressure from members of the family or transplant team. He/she should also be assigned advocates who constantly promote the donor's best interest. Failure to adhere to strict donor evaluation protocols and standardized operative techniques could result in disastrous consequences.

Patients with cryptogenic cirrhosis (CC) comprise a significant proportion of liver transplant recipients. Poor outcome after transplantation has been reported by some centers, with fibrosis occurring in a significant proportion of patients. Outcome of 46 patients with CC who underwent transplantation between 1989 and 1999 at King's College Hospital London were compared with time-matched recipients who underwent transplantation for hepatitis C virus (HCV) cirrhosis (n = 58) and patients with alcohol-related cirrhosis (AC, n = 53) during the same time period. Mean follow-up was 46 +/- 37 months for CC patients, 41 +/- 31 months for AC patients, and 49 +/- 31 months for HCV patients. No protocol liver biopsy specimens were obtained, and biopsies were performed only for investigation of biochemical abnormalities. Acute cellular rejection occurred in 30% of CC, 26% of AC, and 37% of HCV patients (P = NS). Overall patient and graft survival at 1 year was 85% and 80% for CC patients, 87% and 81% for AC patients, and 91% and 82% for patients with HCV (P = NS). Five-year patient and graft survival was 81% and 77% for CC patients, 60% and 48% for AC patients, and 79% and 57% for HCV patients (Log rank; P =.369). Twenty-two percent of CC patients had inflammation on last evaluable liver biopsy, compared with 25% of patients who underwent transplantation for AC and 68% of patients who underwent transplantation for HCV. No patient who underwent transplantation for CC had histologic evidence of cirrhosis on last evaluable biopsy, compared with 2% of patients who underwent transplantation for AC and 16% of patients who underwent transplantation for HCV (Chi-squared = 13.053, P =.0015). These results suggest that CC is a favorable indication for OLT and that although a proportion of patients develop inflammation in the liver allograft, this does not result in significant graft dysfunction or loss.