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Introduction: Access to Liver transplantation (LT) can be affected by several barriers, resulting in delayed referral and increased risk of mortality due to complications of the underlying liver disease., Aim: To assess the clinical characteristics and outcomes of patients with acute or chronic liver disease referred using an integrated referral program., Materials and Methods: An integrated referral program was developed in 1 October 2017 based on email addresses and a 24/7 telephone availability. All consecutive adult patients with liver disease referred for the first time using this referral program were prospectively collected until 1 October 2021. Characteristics and outcomes of inpatients were compared with a historical cohort of patients referred without using the integrated referral program (1 October 2015-1 October 2017). Patients were further divided according to pre- and post-Covid-19 pandemic., Results: Two hundred eighty-one referred patients were considered. End stage liver disease was the most common underlying condition (79.3%), 50.5% of patients were referred as inpatients and 74.7% were referred for LT evaluation. When inpatient referrals (n = 142) were compared with the historical cohort (n = 86), a significant increase in acute liver injury due to drugs/herbals and supplements was seen (p = 0.01) as well as an increase in End stage liver disease due to alcohol-related liver disease and NASH, although not statistically significant. A significant increase in referrals for evaluation for Trans-jugular intrahepatic portosystemic shunt placement was seen over time (5.6% vs. 1%; p = 0.01) as well as for LT evaluation (84.5% vs. 81%; p = 0.01). Transplant-free survival was similar between the study and control groups (p = 0.3). The Covid-19 pandemic did not affect trends of referrals and patient survival., Conclusions: The development of an integrated referral program for patients with liver disease can represent the first step to standardize already existing referral networks between hub and spoke centers. Future studies should focus on the timing of referral according to different etiologies to optimize treatment options and outcomes., (© 2023 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Background and Aims: Fatty liver disease is a major public health threat due to its very high prevalence and related morbidity and mortality. Focused and dedicated interventions are urgently needed to target disease prevention, treatment, and care., Approach and Results: We developed an aligned, prioritized action agenda for the global fatty liver disease community of practice. Following a Delphi methodology over 2 rounds, a large panel (R1 n = 344, R2 n = 288) reviewed the action priorities using Qualtrics XM, indicating agreement using a 4-point Likert-scale and providing written feedback. Priorities were revised between rounds, and in R2, panelists also ranked the priorities within 6 domains: epidemiology, treatment and care, models of care, education and awareness, patient and community perspectives, and leadership and public health policy. The consensus fatty liver disease action agenda encompasses 29 priorities. In R2, the mean percentage of "agree" responses was 82.4%, with all individual priorities having at least a super-majority of agreement (> 66.7% "agree"). The highest-ranked action priorities included collaboration between liver specialists and primary care doctors on early diagnosis, action to address the needs of people living with multiple morbidities, and the incorporation of fatty liver disease into relevant non-communicable disease strategies and guidance., Conclusions: This consensus-driven multidisciplinary fatty liver disease action agenda developed by care providers, clinical researchers, and public health and policy experts provides a path to reduce the prevalence of fatty liver disease and improve health outcomes. To implement this agenda, concerted efforts will be needed at the global, regional, and national levels., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background & Aims: Comparative assessments of immunogenicity following different COVID-19 vaccines in patients with distinct liver diseases are lacking. SARS-CoV-2-specific T-cell and antibody responses were evaluated longitudinally after one to three vaccine doses, with long-term follow-up for COVID-19-related clinical outcomes., Methods: A total of 849 participants (355 with cirrhosis, 74 with autoimmune hepatitis [AIH], 36 with vascular liver disease [VLD], 257 liver transplant recipients [LTRs] and 127 healthy controls [HCs]) were recruited from four countries. Standardised immune assays were performed pre and post three vaccine doses (V1-3)., Results: In the total cohort, there were incremental increases in antibody titres after each vaccine dose (p <0.0001). Factors associated with reduced antibody responses were age and LT, whereas heterologous vaccination, prior COVID-19 and mRNA platforms were associated with greater responses. Although antibody titres decreased between post-V2 and pre-V3 (p = 0.012), patients with AIH, VLD, and cirrhosis had equivalent antibody responses to HCs post-V3. LTRs had lower and more heterogenous antibody titres than other groups, including post-V3 where 9% had no detectable antibodies; this was heavily influenced by intensity of immunosuppression. Vaccination increased T-cell IFNγ responses in all groups except LTRs. Patients with liver disease had lower functional antibody responses against nine Omicron subvariants and reduced T-cell responses to Omicron BA.1-specific peptides compared to wild-type. 122 cases of breakthrough COVID-19 were reported of which 5/122 (4%) were severe. Of the severe cases, 4/5 (80%) occurred in LTRs and 2/5 (40%) had no serological response post-V2., Conclusion: After three COVID-19 vaccines, patients with liver disease generally develop robust antibody and T-cell responses to vaccination and have mild COVID-19. However, LTRs have sustained no/low antibody titres and appear most vulnerable to severe disease., Impact and Implications: Standardised assessments of the immune response to different COVID-19 vaccines in patients with liver disease are lacking. We performed antibody and T-cell assays at multiple timepoints following up to three vaccine doses in a large cohort of patients with a range of liver conditions. Overall, the three most widely available vaccine platforms were immunogenic and appeared to protect against severe breakthrough COVID-19. This will provide reassurance to patients with chronic liver disease who were deemed at high risk of severe COVID-19 during the pre-vaccination era, however, liver transplant recipients had the lowest antibody titres and remained vulnerable to severe breakthrough infection. We also characterise the immune response to multiple SARS-CoV-2 variants and describe the interaction between disease type, severity, and vaccine platform. These insights may prove useful in the event of future viral infections which also require rapid vaccine development and delivery to patients with liver disease., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Alcohol-related liver disease (ArLD) is a major cause of chronic liver disease globally. Traditionally, ArLD was mostly a concern in men rather than in women; however, such a sex gap is rapidly narrowing due to increasing chronic alcohol consumption among women. Female sex is more vulnerable to the harmful effects of alcohol with a higher risk of progression to cirrhosis and development of associated complications. The relative risk of cirrhosis and liver-related mortality is significantly higher in women than in men. Our review endeavors to summarize the current knowledge on sex differences in alcohol metabolism, pathogenesis of ArLD, disease progression, indication for liver transplant and pharmacological treatments of ArLD, and provide evidence in support of a sex-specific management of these patients., (© 2023 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Vascular liver diseases are an heterogenous group of diseases that collectively represent an important health issue in the field of liver diseases. This narrative review was elaborated by the Special Interest Group (SIG) "Gender in Hepatology" of the Italian Association for the Study of the Liver (AISF). We aimed to review the current knowledge regarding the potential role of biological sex in patients with vascular liver diseases such as splanchnic vein thrombosis, hepatic vein thrombosis, porto-sinusoidal vascular disorder, and hereditary hemorrhagic telangiectasia. As vascular liver diseases commonly affect young individuals, including women in childbearing age, we also included a specific section on the management of pregnancy in these challenging patients., Competing Interests: Conflict of interest None declared., (Copyright © 2022. Published by Elsevier Ltd.)

The integration of human and artificial intelligence (AI) in medicine has only recently begun but it has already become obvious that intelligent systems can dramatically improve the management of liver diseases. Big data made it possible to envisage transformative developments of the use of AI for diagnosing, predicting prognosis and treating liver diseases, but there is still a lot of work to do. If we want to achieve the 21 st century digital revolution, there is an urgent need for specific national and international rules, and to adhere to bioethical parameters when collecting data. Avoiding misleading results is essential for the effective use of AI. A crucial question is whether it is possible to sustain, technically and morally, the process of integration between man and machine. We present a systematic review on the applications of AI to hepatology, highlighting the current challenges and crucial issues related to the use of such technologies., Competing Interests: Conflict of interest The research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021. Published by Elsevier Ltd.)

Competing Interests: Declarations of interests IG received support from Fundacion de Investigacion sanitaria and was cofunded by Instituto Carlos III for the present manuscript; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Gilead Sciences, Intercept, and AbbVie; and support for attending meetings or travel from Intercept and Gilead Sciences. EB received grants or contracts from Gilead Sciences; received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Gilead Sciences and Novo Nordisk; and participated on Data Safety Monitoring Boards or advisory boards for Bristol Myers Squibb, Boehringer Ingelheim, Gilead Sciences, Intercept, Inventiva, and Novo Nordisk. MC received grants or contracts and support for attending meetings or travel from the OECD programme of work for public health. RF received grants or contracts from Gilead Sciences, AbbVie, Roche, and Merck Sharp & Dohme; consulting fees from Gilead Sciences, AbbVie, Janssen, and Pfizer; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Gilead Sciences, AbbVie, Merck Sharp & Dohme, and AdamedPG; and support for attending meetings or travel from Gilead Sciences, AbbVie, and Merck Sharp & Dohme. JVL received grants or contracts from AbbVie, Gilead Sciences, Merck Sharp & Dohme; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AbbVie, Gilead Sciences, Intercept, Janssen, and Merck Sharp & Dohme. AL received grants or contracts from the OECD programme of work for public health, which is supported by Ministries of Health, National Governmental Institutions, and intergovernmental organisations, as well as support to present results from OECD analyses to meetings, seminars, and workshops. CL received grants or contracts from the University of Oxford, UK National Centre for Smoking Cessation and Training, and Horizon 2020 of the European Commission; received royalties or licenses from and has patents planned, issued, or pending with Olvos Science (Cretan Iama); received payment for expert testimony from WHO and the European Commission; and participated on Data Safety Monitoring Boards or advisory boards for Merck Sharp & Dohme, Pfizer Hellas, Vianex. MPM received grants or contracts from AbbVie, Eiger BioPharmaceuticals, Bristol Myers Squibb, Dr Falk Pharma, Gilead Sciences, Intercept, Merck Sharp & Dohme, and Roche; received consulting fees from AbbVie, Bristol Myers Squibb, Dr Falk Pharma, Gilead Sciences, Intercept, Merck Sharp & Dohme, Novartis, and Roche; received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AbbVie, Bristol Myers Squibb, Dr Falk Pharma, Gilead Sciences, Merck Sharp & Dohme, and Roche; received support for attending meetings or travel from AbbVie, Bristol Myers Squibb, Dr Falk Pharma, Gilead Sciences, Merck Sharp & Dohme, and Roche; participated on Data Safety Monitoring Boards or advisory boards for Eiger, Dr Falk Pharma, Gilead Sciences, and Roche; and is Associate Editor for Clinical Gastroenterology and Hepatology. NKM received grants or contracts from Merck Sharp & Dohme and Gilead Sciences. MN received grants or contracts from Gilead Sciences, Merck Sharp & Dohme, AbbVie, and Janssen; and was President of the World Hepatitis Alliance (2018–20). CYP received grants or contracts from Takeda, Pliant, and Gilead Sciences; consulting fees from Pliant and Shire (Takeda); and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Takeda, Tillotts Pharma, and Pfizer. BSa received grants or contracts from Bristol Myers Squibb and Sirtex Medical; received consulting fees from Adaptimmune, AstraZeneca, Bayer, Bristol Myers Squibb, BTG, Sirtex Medical, TERUMO, H3 Biomedicine, Incyte, Ipsen, Lilly, and Roche; received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Bayer, Bristol Myers Squibb, Sirtex Medical, TERUMO, Incyte, and Ipsen; and participated on Data Safety Monitoring Boards or advisory boards for Adaptimmune, AstraZeneca, Bayer, Bristol Myers Squibb, BTG, Sirtex Medical, TERUMO, H3 Biomedicine, Incyte, Ipsen, Lilly, and Roche. CS received grants or contracts from BiomX and Galapagos; consulting fees from BiomX; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Falk Foundation. NSc received grants or contracts from Gilead Sciences. MS-B received grants or contracts from the European Commission. CT received grants or contracts from Merck Sharp & Dohme; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Gilead Sciences and AbbVie. RB received consulting fees from WHO. HC-P received consulting fees from Orphalan; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Orphalan, Novo Nordisk, GENFIT, Promethera Biosciences, and Intercept. GD received consulting fees from Aligos Therapeutics, Roche, Arbutus Biopharma, Gilead Sciences, Shionogi, Antios Therapeutics; received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Gilead Sciences; and participated on Data Safety Monitoring Boards or advisory boards for Janssen, Pharmaceuticals, GlaxoSmithKline, and Aligos Therapeutics. THK received consulting fees from Engitix and Intercept; has stock or stock options in Ultimovacs; received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Gilead Sciences, Novartis, and AlfaSigma; and is on the board of the Biomedical Alliance in Europe. ES received consulting fees from Albireo, Mirum, and Alexion; received support for attending meetings or travel from Astellas; participated on Data Safety Monitoring Boards or advisory boards for Albireo, Alexion, and Mirum; and received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Albireo. PB received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Kedrion Biopharma, Biotest, and Chiesi Farmaceutici. MB received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Gilead Sciences and AbbVie. SJH received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Gilead Sciences. NF participated on Data Safety Monitoring Boards or advisory boards for Intercept in relation to NAFLD. GM participated on Data Safety Monitoring Boards or advisory boards for Gilead Sciences, Novartis, Pfizer, and AstraZeneca. All other authors declare no competing interests.

Liver and kidney are strictly connected in a reciprocal manner, in both the physiological and pathological condition. The Italian Association for the Study of Liver, in collaboration with the Italian Society of Nephrology, with this position paper aims to provide an up-to-date overview on the principal relationships between these two important organs. A panel of well-recognized international expert hepatologists and nephrologists identified five relevant topics: 1) The diagnosis of kidney damage in patients with chronic liver disease; 2) Acute kidney injury in liver cirrhosis; 3) Association between chronic liver disease and chronic kidney disease; 4) Kidney damage according to different etiology of liver disease; 5) Polycystic kidney and liver disease. The discussion process started with a review of the literature relating to each of the five major topics and clinical questions and related statements were subsequently formulated. The quality of evidence and strength of recommendations were graded according to the GRADE system. The statements presented here highlight the importance of strong collaboration between hepatologists and nephrologists for the management of critically ill patients, such as those with combined liver and kidney impairment., Competing Interests: Declaration of Competing Interest Maria Cristina Morelli: has served on advisory boards for Abbvie, Gilead sciences, Shionogi srl. Carlo Alessandria: reports personal fees from Alfasigma, outside the submitted work. Sherrie Bhoori: has served as speaker bureau for Boston Scientific, Eisai, Ipsen, Kedrion. Salvatore Petta: has served as Advisor and/or Speaker for AbbVie, Gilead, Intercept and Pfyze.r Patrizia Burra: has served as Advisor and/or Speaker for Kedrion, Biotest and Chiesi Farmaceutici. Maria Rendina, Ilaria Lenci, Piergiorgio Messa, Loreto Gesualdo, Francesco Paolo Russo Luisa Pasulo, Gaetano La Manna, Luigi Biancone: none to disclose., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The vaccination campaign against Sars-CoV-2 commenced in Italy at the end of December 2020. The first ones to receive the immunization against the virus were the health workers and the residents of nursing homes, following which the vaccine would be available for the entire population, beginning with the most vulnerable individuals. SARS-CoV2 vaccines have been demonstrated to be safe for the general population, although no data for patients with liver diseases or those having undergone liver transplantation are available so far. The present position statement AISF is an attempt to suggest, based on the published data on the impact of Sars-Cov-2 infection in patients with chronic liver disease, a possible priority for vaccination for this category of patients., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Portal vein thrombosis (PVT) is the most common thrombotic event in liver transplant (LT) recipients, but its impact on mortality after LT has been analyzed in heterogeneous cohorts with mixed results. To conduct a meta-analysis on the impact of PVT on post-LT survival. A systematic search was conducted on studies (published from January 1986 to January 2018) that reported 30-day and 1-year mortality after LT of PVT patients. Four hundred twenty-seven articles were reviewed and 44 were included. Among 98 558 LT, 7257 (7.3%) involved patients with PVT. The mean quality was high (7.1 on the Newcastle-Ottawa scale). The 30-day pooled mortality rate was higher for patients with PVT (64/490; 13%) than for others (259/3357; 7%) (OR 2.29; 95% CI 1.43-3.68; P < 0.0001). One-year mortality was likewise higher in recipients with (853/6302; 13.5%) than in those without PVT (7476/75 355; 9.9%) (OR 1.38; 95% CI 1.14-1.66; P < 0.0001). Heterogeneity wasn't significant (I 2 46% and 65%). Patients whose PVT was complete had a higher 30-day pooled mortality rate (OR 5.65; 95% CI 2-15.96; P < 0.0001), and a 1-year mortality rate (OR 2.48; 95% CI 0.99-6.17; P = 0.38) than patients with partial PVT. PVT is common in LT candidates and it is associated with higher short- and medium-term mortality after LT., (© 2018 Steunstichting ESOT.)

Background: Medical advances have dramatically improved the long-term prognosis of children and adolescents with once-fatal hepatobiliary diseases. However, there is no generally accepted optimal pathway of care for the transition from paediatric care to the adult health system., Aim: The purpose of this position paper is to propose a transition process for young people with paediatric onset hepatobiliary diseases from child-centred to adult-centred healthcare services., Methods: Seventeen ESPGHAN/EASL physicians from 13 countries (Austria, Belgium, France, Germany, Hungary, Italy, the Netherlands, Norway, Poland, Spain, Sweden, Switzerland, and United Kingdom) formulated and answered questions after examining the currently published literature on transition from childhood to adulthood. PubMed and Google Scholar were systematically searched between 1980 and January 2018. Quality of evidence was assessed by the Grading of Recommendation Assessment, Development and Evaluation (GRADE) system. Expert opinions were used to support recommendations whenever the evidence was graded weak. All authors voted on each recommendation, using the nominal voting technique., Results: We reviewed the literature regarding the optimal timing for the initiation of the transition process and the transfer of the patient to adult services, principal documents, transition multi-professional team components, main barriers, and goals of the general transition process. A transition plan based on available evidence was agreed focusing on the individual young people's readiness and on coordinated teamwork, with transition monitoring continuing until the first year of adult services.We further agreed on selected features of transitioning processes inherent to the most frequent paediatric-onset hepatobiliary diseases. The discussion highlights specific clinical issues that will probably present to adult gastrointestinal specialists and that should be considered, according to published evidence, in the long-term tracking of patients., Conclusions: Transfer of medical care of individuals with paediatric onset hepatobiliary chronic diseases to adult facilities is a complex task requiring multiple involvements of patients and both paediatric and adult care providers.

The liver and its pleotropic functions play a fundamental role in regulating metabolism, and is also an inevitable target of multiple metabolic disorders. The numerous and constant relationships and feedback mechanisms between the liver and all endocrine organs is reflected by the fact that an alteration of one oftentimes results in the malfunction of the other. Hypo- and hyperthyroidism are frequently associated with hepatic alterations, and thyroid diseases must be excluded in transaminase elevation of unknown cause. Drugs such as propylthiouracil, used in the treatment of hyperthyroidism, may induce liver damage, and other drugs such as amiodarone, carbamazepine, and several chemotherapeutic agents can lead to both thyroid and liver abnormalities. Liver diseases such as hepatitis, hepatocellular carcinoma, and cirrhosis may cause altered levels of thyroid hormones, and alcoholic liver disease, both due to the noxious substance ethanol as well as to the hepatic damage it causes, may be responsible for altered thyroid function. Both excess and insufficiency of adrenal function may result in altered liver function, and adrenocortical dysfunction may be present in patients with cirrhosis, especially during episodes of decompensation. Again an important player which affects both the endocrine system and the liver, alcohol may be associated with pseudo-Cushing syndrome. Sex hormones, both intrinsic as well as extrinsically administered, have an important impact on liver function. While oestrogens are related to cholestatic liver damage, androgens are the culprit of adenomas and hepatocellular carcinoma, among others. Chronic liver disease, on the other hand, has profound repercussions on sex hormone metabolism, inducing feminization in men and infertility and amenorrhoea in women. Lastly, metabolic syndrome, the pandemia of the present and future centuries, links the spectrum of liver damage ranging from steatosis to cirrhosis, to the array of endocrine alterations that are features of the syndrome, including insulin resistance, central obesity, and hyperlipidaemia. Clinical practice must integrally evaluate the effects of the intricate and tight relationship between the liver and the endocrine system, in order to better address all manifestations, complications, and prevent deterioration of one or the other organ-system., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Women constitute a particular group among patients with chronic liver disease and in the post-liver transplantation (LT) setting: they are set apart not only by traditional differences with respect to men (ie, body mass index, different etiologies of liver disease, and accessibility to transplantation) but also in increasingly evident ways related to hormonal changes that characterize first the fertile age and subsequently the postmenopausal period (eg, disease course variability and responses to therapy). The aim of this review is, therefore, to evaluate the role of the interplay of factors such as age, gender, and hormones in influencing the natural history of chronic liver disease before and after LT and their importance in determining outcomes after LT. As the population requiring LT ages and the mean age at transplantation increases, older females are being considered for transplantation. Older patients are at greater risk for nonalcoholic steatohepatitis, osteoporosis, and a worse response to antiviral therapy. Female gender per se is associated with a greater risk for osteoporosis because of metabolic changes after menopause, the bodily structure of females, and, in the population of patients with chronic liver disease, the greater prevalence of cholestatic and autoimmune liver diseases. With menopause, the fall of protective estrogen levels can lead to increased fibrosis progression, and this represents a negative turning point for women with chronic liver disease and especially for patients with hepatitis C. Therefore, the notion of gender as a binary female/male factor is now giving way to the awareness of more complex disease processes within the female gender that follow hormonal, social, and age patterns and need to be addressed directly and specifically., (Copyright © 2012 American Association for the Study of Liver Diseases.)

The goal of liver transplantation is not only to ensure patient long-term survival but also to offer the opportunity to achieve psychologic and physical integrity. Quality of life after liver transplantation may be affected by unsatisfactory sexual function. Before liver transplantation, sexual dysfunction and sex hormone disturbances are reported in men and women mainly due to abnormality of physiology of the hypothalamic-pituitary-gonadal axis and, in some cases, origin of liver disease. Successful liver transplantation should theoretically restore hormonal balance and improve sexual function both in men and women, thus improving the reproductive performance. However, after transplantation, up to 25% of patients report persistent sexual dysfunction, and approximately one third of patients describe the appearance of de novo sexual dysfunction. Despite the described high prevalence of this condition, epidemiologic data are relatively scant. Further studies on pathophysiology and risk factors in the field of sexual function after liver transplantation along with new strategies to support and inform patients on the waiting list and after surgery are needed.

Liver transplantation (LT) has significantly transformed the prognosis of patients with end-stage liver disease and hepatocellular carcinoma (HCC). The traditional epidemiology of liver diseases has undergone a remarkable shift in indications for LT, marked by a decline in viral hepatitis and an increase in metabolic dysfunction-associated steatotic liver disease (MASLD), along with expanded indications for HCC. Recent advancements in surgical techniques, organ preservation and post-transplant patients' management have opened new possibilities for LT. Conditions that were historically considered absolute contraindications have emerged as potential new indications, demonstrating promising results in terms of patient survival. While these expanding indications provide newfound hope, the ethical dilemma of organ scarcity persists. Addressing this requires careful consideration and international collaboration to ensure equitable access to LT. Multidisciplinary approaches and ongoing research efforts are crucial to navigate the evolving landscape of LT. This review aims to offer a current overview of the primary emerging indications for LT, focusing on acute-on-chronic liver failure (ACLF), acute alcoholic hepatitis (AH), intrahepatic and perihilar cholangiocarcinoma (i- and p-CCA), colorectal liver metastasis (CRLM), and neuroendocrine tumor (NET) liver metastases. [ABSTRACT FROM AUTHOR]

Autoimmune liver diseases (AILDs) include autoimmune hepatitis, primary biliary cholangitis and primary sclerosing cholangitis. The etiologies of AILD are not well understood but appear to involve a combination of genetic and environmental factors. AILDs commonly affect young individuals and are characterized by a highly variable clinical course. These diseases significantly influence quality of life and can progress toward liver decompensation or the onset of hepatocellular or cholangiocarcinoma; a significant number of patients eventually progress to end-stage liver disease, requiring liver transplantation. In this review, we focus on the sex characteristics and peculiarities of AILD patients and highlight the relevance of a sex-specific analysis in future studies. Understanding the sex differences underlying AILD immune dysregulation may be critical for developing more effective treatments. [ABSTRACT FROM AUTHOR]

In patients with cirrhosis, particularly those with hepatocellular carcinoma (HCC), hypercoagulability may be associated with purported increased risks of portal vein thrombosis and cirrhosis progression. In this study, we extensively investigated hemostatic alterations potentially responsible for the thrombotic tendency in HCC, and evaluated whether such alterations were predictive of hepatic decompensation. Patients with cirrhosis at all stages were prospectively recruited and underwent an extensive hemostatic assessment, including all procoagulant factors and inhibitors, thrombin generation with and without thrombomodulin (TG), profibrinolytic and antifibrinolytic factors, and plasmin‐antiplasmin complex. In study part 1 (case control), we compared alterations of coagulation and fibrinolysis in patients with cirrhosis with versus without HCC. In study part 2 (prospective), the subgroup of patients with decompensated cirrhosis was followed for development of further decompensation, and predictors of outcome were assessed by multivariate analysis. One‐hundred patients were recruited (50 each with and without HCC). Severity of cirrhosis was comparable between groups. Median HCC volume was 9 cm3 (range: 5‐16). Compared with controls, patients with HCC demonstrated a significantly more prothrombotic hemostatic profile due to increased TG and reduced activation of fibrinolysis, independent of cirrhosis stage. During a median follow‐up of 175 days, 20 patients with decompensated cirrhosis developed further episodes of decompensation that were predicted by low FVII and high plasminogen activator inhibitor‐1 levels, independent of Model for End‐Stage Liver Disease score. Conclusion: Patients with cirrhosis with HCC have profound hyper‐coagulable changes that can account for their increased thrombotic tendency. In contrast, hypercoagulability in patients with decompensated cirrhosis is more likely a consequence of chronic liver disease rather than a driver for cirrhosis progression. [ABSTRACT FROM AUTHOR]

Serum biomarkers have suboptimal accuracy for the early diagnosis of bacterial infection (BI) in cirrhosis. The aim of the study was to evaluate the diagnostic and prognostic accuracy of presepsin (PSP) in a cohort of hospitalized patients with cirrhosis. All adult cirrhotics admitted between 03.2016 and 06.2019 were consecutively evaluated. PSP was measured using chemiluminescent enzyme immunoassay, and its accuracy was compared with that of common biomarkers. A total of 278 cirrhotic patients for a total of 448 hospitalizations were prospectively collected. Prevalence of BI at admission was 28.3%. Median (range) Log10PSP in the whole cohort was 2.83 (2.48–3.19) ng/L, significantly higher in patients with BI than in patients without (p<0.001). For a cutoff value of 2.87 ng/L, Log10PSP showed sensitivity, specificity and AUC-ROC of 0.66 (95% CI 0.57–0.74), 0.63 (95% CI 0.57–0.68) and 0.69 (95% CI 0.63–0.73), lower than that of C-reactive protein (p=0.002), but similar to procalcitonin (p=0.18) Patients with BI at hospitalization had higher probability of 28-day mortality (sub-hazard ratio [sHR] 2.65;95% CI 1.49–4.70; p=0.001). At multivariate Cox's regression analysis, Log10PSP (sHR 2.4; 95% CI 1.22–4.82; p=0.01) together with age and severity of liver disease, was an independent predictor of short-term mortality. PSP shows low diagnostic accuracy for BI in cirrhosis, but it is an independent predictor of short-term mortality. PSP may be a biomarker of systemic inflammation, commonly seen in end-stage liver disease. [ABSTRACT FROM AUTHOR]

Background We analyzed the impact of continuous/extended infusion (C/EI) vs intermittent infusion of piperacillin-tazobactam (TZP) and carbapenems on 30-day mortality of patients with liver cirrhosis and bloodstream infection (BSI). Methods The BICRHOME study was a prospective, multicenter study that enrolled 312 cirrhotic patients with BSI. In this secondary analysis, we selected patients receiving TZP or carbapenems as adequate empirical treatment. The 30-day mortality of patients receiving C/EI or intermittent infusion of TZP or carbapenems was assessed with Kaplan-Meier curves, Cox-regression model, and estimation of the average treatment effect (ATE) using propensity score matching. Results Overall, 119 patients received TZP or carbapenems as empirical treatment. Patients who received C/EI had a significantly lower mortality rate (16% vs 36%, P =.047). In a Cox-regression model, the administration of C/EI was associated with a significantly lower mortality (hazard ratio [HR], 0.41; 95% confidence interval [CI], 0.11–0.936; P =.04) when adjusted for severity of illness and an ATE of 25.6% reduction in 30-day mortality risk (95% CI, 18.9–32.3; P <.0001) estimated with propensity score matching. A significant reduction in 30-day mortality was also observed in the subgroups of patients with sepsis (HR, 0.21; 95% CI, 0.06–0.74), acute-on-chronic liver failure (HR, 0.29; 95% CI, 0.03–0.99), and a model for end-stage liver disease score ≥25 (HR, 0.26; 95% CI, 0.08–0.92). At competing risk analysis, C/EI of beta-lactams was associated with significantly higher rates of hospital discharge (subdistribution hazard [95% CI], 1.62 [1.06–2.47]). Conclusions C/EI of beta-lactams in cirrhotic patients with BSI may improve outcomes and facilitate earlier discharge. [ABSTRACT FROM AUTHOR]

Introduction: In the last years, nonalcoholic steatohepatitis (NASH) has become a leading indication for liver transplant (LT). After transplant, both recurrent and de novo nonalcoholic fatty liver disease (NAFLD) can be commonly diagnosed. However, dedicated surveillance programs for patients with pre- or post-transplant NAFLD are not available. Areas covered: Patients waiting for LT for NASH show specific peculiarities and would deserve targeted stratification of mortality risk. Obesity, hyperlipidemia, and diabetes mellitus can be often found after transplant. These conditions, together with immunosuppressive regimen, make LT recipients a high-risk population for both recurrent and de novo NAFLD. Development of fatty liver disease after LT has a relevant impact on both morbidity and mortality. Expert commentary: A targeted stratification of neoplastic and cardiovascular risk for patients with NASH waiting for LT would be mandatory. In both pre- and post-transplant period, NAFLD should be considered not only a liver disease but also a cardiovascular risk factor. Patients within Transplant Program, especially those with known metabolic risk factors, should be followed with personalized diagnostic and life-style interventions before and after LT. [ABSTRACT FROM AUTHOR]

The discrepancy between the number of patients awaiting liver transplantation and the number of available donors has become a key issue in the transplant setting. Various strategies to cope with the donor shortage problem and to increase the use of suboptimal grafts have been explored.Machine perfusion has been applied ex situ to liver grafts in the effort to improve static cold-storage preservation. If a more extensive application of this technology confirms the preliminary results, machine perfusion will become crucial in increasing the donor pool as well as improving recipients' outcomes. In this review, the authors focused on the evolution ofmachine perfusion, from the first animal experiences to the latest evidence in humans, highlighting the pros and cons aswell as the potential clinical applications of various types of machine. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma is one of the main important causes of cancer-related death and its mortality is increasingly worldwide. In Europe, alcohol abuse accounts for approximately half of all liver cancer cases and it will become the leading cause of hepatocellular carcinoma in the next future with the sharp decline of chronic viral hepatitis. The pathophysiology of alcohol-induced carcinogenesis involves acetaldehyde catabolism, oxidative stress and chronic liver inflammation. Genetic background plays also a significant role and specific patterns of gene mutations in alcohol-related hepatocellular carcinoma have been characterized. Survival is higher in patients who undergo specific surveillance programmes than in patients who do not. However, patients with alcohol cirrhosis present a significantly greater risk of liver decompensation than those with cirrhosis due to other aetiologies. Furthermore, the adherence to screening program can be suboptimal. Liver transplant for patients with Milan-in hepatocellular carcinoma represents the best possible treatment in case of tumour recurrence/progression despite loco-regional or surgical treatments. Long-term result after liver transplantation for alcohol related liver disease is good. However, cardiovascular disease and de novo malignancies can significantly hamper patients' survival and should be carefully considered by transplant team. In this review, we have focused on the evolution of alcohol-related hepatocellular carcinoma epidemiology and risk factors as well as on liver transplantation in alcoholic patients with and without hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

This study quantified the risk of head and neck ( HN) and esophageal cancers in 2770 Italian liver transplant ( LT) recipients. A total of 186 post-transplant cancers were diagnosed-including 32 cases of HN cancers and nine cases of esophageal carcinoma. The 10-year cumulative risk for HN and esophageal carcinoma was 2.59%. Overall, HN cancers were nearly fivefold more frequent in LT recipients than expected (standardized incidence ratios - SIR=4.7, 95% CI: 3.2-6.6), while esophageal carcinoma was ninefold more frequent ( SIR=9.1, 95% CI: 4.1-17.2). SIRs ranged from 11.8 in LT with alcoholic liver disease ( ALD) to 1.8 for LT without ALD for HN cancers, and from 23.7 to 2.9, respectively, for esophageal carcinoma. Particularly elevated SIRs in LT with ALD were noted for carcinomas of tongue (23.0) or larynx (13.7). Our findings confirmed and quantified the large cancer excess risk in LT recipients with ALD. The risk magnitude and the prevalence of ALD herein documented stress the need of timely and specifically organized programs for the early diagnosis of cancer among LT recipients, particularly for high-risk recipients like those with ALD. [ABSTRACT FROM AUTHOR]

Background & Aims The model for end-stage liver disease ( MELD) is used for organ allocation in liver transplantation ( LT), but its prognostic performance is less accurate in patients with low score. We assess the outcome of patients with MELD < 18 awaiting LT, finding prognostic variables to identify a high dropout risk. Methods Training set consisted of 277 patients and validation cohort of 292 patients. Competing risk regression analysis, taking into account LT, was used for univariate/multivariate analysis. Results Ascites, sodium, bilirubin, albumin and glomerular filtration rate were independently associated with a 12-month dropout risk in the training set. Combining these five prognostic parameters, we calculated a new score named liver-renal-risk ( LIRER). In the validation set, the 12-month LIRER concordance index showed a discrimination power [0.798, 95% confidence interval (95% CI) 0.793-0.803] better than MELD (0.582, 95% CI 0.575-0.588), Child-Turcotte-Pugh (0.687, 95% CI 0.681-0.693), MELD-sodium (0.721, 95% CI 0.715-0.727) and MELD-ascites-sodium (0.729, 95% CI 0.724-0.735), with a remarkable calibration (Hosmer-Lemeshow test: P = 0.91; R2 = 0.911). Considering all study patients, the risk of wait list dropout increased with the rise in LIRER. The survival benefit analysis comparing the wait list dropout risk with the mortality of the 216 transplanted patients with same LIRER showed an important benefit for LT in patients with LIRER > 15.9. Conclusions In patients with low MELD (<18), combination of ascites, sodium, albumin, bilirubin and renal function in a new score ( LIRER) discriminates patients at high risk of medium-term adverse outcome from those in whom LT may be safely deferred. [ABSTRACT FROM AUTHOR]

Allograft dysfunction with clinical, serologic, and histologic features resembling autoimmune hepatitis (AIH) may develop in pediatric and adult patients who have received a liver transplant (LT) for end-stage diseases other than AIH. This condition is now known as de novo AIH, although its pathophysiology is still uncertain and whether it represents a specific type of rejection or a genuine form of AIH is under debate. The occurrence of de novo AIH seems to be unrelated to the etiology of the disease necessitating liver transplantation, but it has been correlated with antiviral treatment in cases of hepatitis C virus (HCV) infection recurring after LT. Several investigators have reported adverse outcome of de novo AIH, including graft failure, particularly in cases with late diagnosis. Prompt treatment with prednisone, with or without azathioprine (in addition to the basic immunosuppressive regimen), seems to be the best option. The histology of de novo AIH is characterized by an infiltrate rich in plasma cells with significant interface hepatitis and perivenular necro-inflammatory activity. These features are not specific for autoimmune damage; therefore, other causes of graft dysfunction must be excluded. The final diagnosis may be a challenge in patients with recurrent hepatitis C, and requires careful clinical and pathologic assessment. [ABSTRACT FROM AUTHOR]

Background: Bax inhibitor-1 (BI-1) is an evolutionary conserved endoplasmic reticulum protein that, when overexpressed in mammalian cells, suppresses the apoptosis induced by Bax, a pro-apoptotic member of the Bcl-2 family. The aims of this study were: (1) to clarify the role of intrinsic anti- and pro-apoptotic mediators, evaluating Bax and BI-1 mRNA and protein expressions in liver tissues from patients with different degrees of liver damage; (2) to determine whether HCV and HBV infections modulate said expression. Methods: We examined 62 patients: 39 with chronic hepatitis (CH) (31 HCV-related and 8 HBV-related); 7 with cirrhosis (6 HCV-related and 1 HBV-related); 13 with hepatocellular carcinoma (HCC) [7 in viral cirrhosis (6 HCV- and 1 HBVrelated), 6 in non-viral cirrhosis]; and 3 controls. Bax and BI-1 mRNAs were quantified by real-time PCR, and BI-1 protein expression by Western blot. Results: CH tissues expressed significantly higher BI-1 mRNA levels than cirrhotic tissues surrounding HCC (P < 0.0001) or HCC (P < 0.0001). Significantly higher Bax transcripts were observed in HCV-genotype-1-related than in HCVgenotype- 3-related CH (P = 0.033). A positive correlation emerged between BI-1 and Bax transcripts in CH tissues, even when HCV-related CH and HCV-genotype-1-related CH were considered alone (P = 0.0007, P = 0.0005 and P = 0.0017, respectively). Conclusions: BI-1 expression is down-regulated as liver damage progresses. The high BI-1 mRNAs levels observed in early liver disease may protect virus-infected cells against apoptosis, while their progressive downregulation may facilitate hepatocellular carcinogenesis. HCV genotype seems to have a relevant role in Bax transcript expression. [ABSTRACT FROM AUTHOR]

Introduction: Bacterial infections have been hypothetized to be a trigger of variceal bleeding in cirrhotic patients and β-blockers may have a protective effect by decreasing bacterial translocation, reducing portal pressure. The aim of our study was to evaluate the possible role of β-blockers in preventing spontaneous bacterial peritonitis (SBP) in patients with liver cirrhosis and ascites. Materials and Methods: Extensive search of the literature including randomized controlled trial (RCT) and non-RCT of primary and secondary prophylaxis for variceal bleeding in cirrhotics using β-blockers were evaluated. We performed a meta-analysis using the occurrence of SBP as endpoint in all the studies, using the random effect model. Results: Three RCT and three retrospective studies in which β-blockers were evaluated against no treatment for the prevention of SBP in ascitic cirrhotics were included. There was a statistically significant difference of 12.1%, P<0.001 in favour of propranolol in preventing SBP, which was confirmed by sensitivity analysis evaluating only RCTs (7.8% difference). The effect was still present when haemodynamic responders were compared with non-responders. Conclusions: This analysis suggests a role of β-blockers in preventing SBP in ascitic cirrhotics, independent of haemodynamic response. Further formal RCTs are needed to confirm this finding. [ABSTRACT FROM AUTHOR]

Few studies have been performed on the prevalence of Torque Teno Virus (TTV) infection in liver transplant (LT) recipients. The aim of this study was to assess the prevalence, viremia and genogroup pattern of TTV among LT patients and to ascertain whether TTV causes liver damage in liver transplanted patients with biochemical and histological changes of unknown origin. Twenty-five patients were evaluated before and after LT; 80 healthy subjects were considered as controls. Serum samples were serially obtained from all the patients before LT and thereafter at 3, 6 and 12 months post-transplant. Serum TTV-DNA and genogroups were assessed by PCR. Patients underwent protocol serial liver biopsies at 6 and 12 months after LT. Results were compared using the Chi-squared tests, McNemar’s and Student’s t-tests. TTV-DNA was found in 25/25 patients before LT and in 60/80 blood donors ( P < 0.01). The TTV-DNA load increased significantly after LT ( P < 0.001). TTV-DNA was significantly higher in patients on calcineurin inhibitors (CNI) and azathioprine or mycophenolate mofetil than in patients on CNI alone ( P = 0.04) at 3 months after LT. Genogroup analysis showed a significant increase in genogroup 5 positivity after LT. No differences were seen in the viremia of patients compared according to their viral versus other etiologies of their liver disease before transplantation. Viremia and TTV genotype patterns did not correlate with the presence of hypertransaminasemia or histological liver damage of unknown etiology. The prevalence of TTV-DNA was significantly higher in patients with liver cirrhosis than in controls and the viral load was significantly higher after LT than beforehand. On the basis of our data, TTV does not seem to cause liver damage following LT, although larger studies with a long-term follow up are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Background & Aims: This study extends our previously reported observations that various immunological factors are associated with the occurrence of histologically proven recurrent hepatitis C. The two specific issues investigated were to confirm the associations of MHC alleles and donor/recipient mismatch with the occurrence of recurrent hepatitis C in an independent cohort of newly transplanted patients and to look for immunologic and nonimmunologic variables affecting the severity of the recurrent disease. Methods: Two separate cohorts of consecutive patients were studied: a look-back cohort (LC) of 120 patients and a cohort for studying the disease progression (CSDP) of 190 patients. Protocol liver biopsies were obtained at least 1, 3, 5, 7, and 10 years after liver transplantation (LT). Results: A fully mismatched donor/recipient pair at the DRB1 locus was confirmed to be associated with both the recurrence of histologic hepatitis in the LC (59% vs 23%, P = .0002) and its progression beyond stage 3 in the CSPD (71.4% vs 39.3%, P = .0003). Relevant immunologic and nonimmunologic variables were included into a multivariate Cox proportional model and three variables, namely, donor age, full HLA-DRB1 donor-recipient mismatch, and HLA B14, resulted in independent risk factors for the development of severe fibrosis. Conclusion: This study provides evidence that DRB1 donor-recipient mismatch affects both the occurrence and progression of recurrent hepatitis C disease. This information is clinically relevant as it may help to better allocate organs and to recognize patients at risk for progression so that specific interventions can be implemented. [Copyright &y& Elsevier]

Alcoholic liver disease is one of the most common causes of cirrhosis and indications for orthotopic liver transplantation in Europe and North America. The reluctance to transplant alcoholics stems in part from the view that alcoholics bear responsibility for their illness. There is also the perception that the alcoholic person is likely to relapse into alcohol use after transplantation and thereby damage the allograft. In this review, we considered the evaluation for and outcome of liver transplantation in alcoholics with special attention to the specific risks of alcohol relapse, to show that alcoholism should be considered like other co-morbid states rather than as a moral flaw. [ABSTRACT FROM AUTHOR]

Reperfusion injury represents a key event leading to graft nonfunction. Maintaining adequate nitric oxide levels and stimulating vasodilator synthesis can probably minimize endothelial damage. The aim of this study was to investigate the effect of L-arginine, a substrate of nitric oxide synthesis, and oligotide, a promoter of prostacyclin synthesis, on liver function and morphology after warm ischemia-reperfusion injury. After constructing a side-to-side portacaval shunt, ischemia was induced by clamping the hepatic hilum for 2 h above the shunt, in 19 female pigs divided into a control group (n = 7), an L-arginine treatment group (n = 6), and an oligotide treatment group (n = 6). Liver function tests and measurements of serum and red blood cell malondialdehyde and plasma nitric oxide levels were performed before reperfusion and at 1, 10, 60, and 120 min after reperfusion. Liver biopsies, taken before reperfusion and at 30 min and 7 days after reperfusion, were analyzed for tissue malondialdehyde, histological-ultrastructural features, and apoptosis evaluation. Thirty minutes after reperfusion, liver malondialdehyde, sinusoidal congestion, necrosis, and apoptosis were significantly lower in the L-arginine group than in the controls (p < .05). On postoperative day 7, tissue malondialdehyde decreased, while plasma nitric oxide and hepatocyte glycogen content were increased in the L-arginine group compared to controls (p < .05). This study demonstrates the protective effect of L-arginine on hepatic lipoperoxidation and liver morphology in a pig model of warm ischemia-reperfusion injury. The increased plasma levels of nitric oxide a week after ischemia-reperfusion injury support the hypothesis that it has a role in preventing liver damage. The same beneficial effect was not confirmed for oligotide. [ABSTRACT FROM AUTHOR]

Liver transplantation (LT) is an important therapeutic option for the treatment of several liver diseases. Modern LT is characterized by remarkable improvements in post-transplant patient survival, graft survival, and quality of life. Thanks to these great improvements, indications for LT are expanding. Nowadays, clinical conditions historically considered exclusion criteria for LT, have been considered new indications for LT, showing survival advantages for patients. In this review, we provide an updated overview of the principal newer indications for LT, with particular attention to alcoholic hepatitis, acute-on-chronic liver failure (ACLF), cholangiocarcinoma and colorectal cancer metastases. [ABSTRACT FROM AUTHOR]

An estimated 38% of adults worldwide have non-alcoholic fatty liver disease (NAFLD). From individual impacts to widespread public health and economic consequences, the implications of this disease are profound. This study aimed to develop an aligned, prioritised fatty liver disease research agenda for the global health community. Nine co-chairs drafted initial research priorities, subsequently reviewed by 40 core authors and debated during a three-day in-person meeting. Following a Delphi methodology, over two rounds, a large panel (R1 n = 344, R2 n = 288) reviewed the priorities, via Qualtrics XM, indicating agreement using a four-point Likert-scale and providing written feedback. The core group revised the draft priorities between rounds. In R2, panellists also ranked the priorities within six domains: epidemiology, models of care, treatment and care, education and awareness, patient and community perspectives, and leadership and public health policy. The consensus-built fatty liver disease research agenda encompasses 28 priorities. The mean percentage of 'agree' responses increased from 78.3 in R1 to 81.1 in R2. Five priorities received unanimous combined agreement ('agree' + 'somewhat agree'); the remaining 23 priorities had >90% combined agreement. While all but one of the priorities exhibited at least a super-majority of agreement (>66.7% 'agree'), 13 priorities had <80% 'agree', with greater reliance on 'somewhat agree' to achieve >90% combined agreement. Adopting this multidisciplinary consensus-built research priorities agenda can deliver a step-change in addressing fatty liver disease, mitigating against its individual and societal harms and proactively altering its natural history through prevention, identification, treatment, and care. This agenda should catalyse the global health community's efforts to advance and accelerate responses to this widespread and fast-growing public health threat. An estimated 38% of adults and 13% of children and adolescents worldwide have fatty liver disease, making it the most prevalent liver disease in history. Despite substantial scientific progress in the past three decades, the burden continues to grow, with an urgent need to advance understanding of how to prevent, manage, and treat the disease. Through a global consensus process, a multidisciplinary group agreed on 28 research priorities covering a broad range of themes, from disease burden, treatment, and health system responses to awareness and policy. The findings have relevance for clinical and non-clinical researchers as well as funders working on fatty liver disease and non-communicable diseases more broadly, setting out a prioritised, ranked research agenda for turning the tide on this fast-growing public health threat. • A large, global multidisciplinary panel reached high agreement levels on 28 fatty liver disease research priorities. • Priorities spanned a broad range of areas, from disease burden and health system responses to policy and treatment. • Consensus increased in all 6 research domains across two voting rounds, from 78.3 in R1 to 81.1 in R2. • The mean level of combined agreement ('agree' + 'somewhat agree') across all priorities in R2 was 97.7%. • All priorities had >90% combined agreement ('agree' + 'somewhat agree') and 5 of these achieved unanimous agreement. [Display omitted] [ABSTRACT FROM AUTHOR]

Summary: This review will highlight some of the important recent trends in liver transplantation. When possible, we will compare and contrast these trends across various regions of the world, in an effort to improve global consensus and better recognition of emerging data. [ABSTRACT FROM AUTHOR]

• An optimal allocation system for scarce resources should simultaneously ensure maximal utility, but also equity. • Large differences exist between centers and countries for ethical and legislative reasons. • A future globally applicable strategy should combine donor and recipient factors. • This strategy must predict probability of death on the waiting list, post-transplant survival and morbidity, and costs. An optimal allocation system for scarce resources should simultaneously ensure maximal utility, but also equity. The most frequent principles for allocation policies in liver transplantation are therefore criteria that rely on pre-transplant survival (sickest first policy), post-transplant survival (utility), or on their combination (benefit). However, large differences exist between centers and countries for ethical and legislative reasons. The aim of this study was to report the current worldwide practice of liver graft allocation and discuss respective advantages and disadvantages. Countries around the world that perform 95 or more deceased donor liver transplantations per year were analyzed for donation and allocation policies, as well as recipient characteristics. Most countries use the model for end-stage liver disease (MELD) score, or variations of it, for organ allocation, while some countries opt for center-based allocation systems based on their specific requirements, and some countries combine both a MELD and center-based approach. Both the MELD and center-specific allocation systems have inherent limitations. For example, most countries or allocation systems address the limitations of the MELD system by adding extra points to recipient's laboratory scores based on clinical information. It is also clear from this study that cancer, as an indication for liver transplantation, requires special attention. The sickest first policy is the most reasonable basis for the allocation of liver grafts. While MELD is currently the standard for this model, many adjustments were implemented in most countries. A future globally applicable strategy should combine donor and recipient factors, predicting probability of death on the waiting list, post-transplant survival and morbidity, and perhaps costs. An optimal allocation system for scarce resources should simultaneously ensure maximal utility, but also equity. While the model for end-stage liver disease is currently the standard for this model, many adjustments were implemented in most countries. A future globally applicable strategy should combine donor and recipient factors predicting probability of death on the waiting list, post-transplant survival and morbidity, and perhaps costs. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • The Psychomotor Vigilance Task (PVT) is a test of vigilance and provides a series of parameters which are stable in the healthy population, regardless of sex, age and level of education. • PVT parameters correlate well with standard measures of hepatic encephalopathy (HE). • PVT parameters may be useful to quantify mild overt HE and identify dangerous drivers among patients with cirrhosis. Background & Aims Hepatic encephalopathy (HE) is a syndrome of decreased vigilance and has been associated with impaired driving ability. The aim of this study was to evaluate the psychomotor vigilance task (PVT), which is used to assess both vigilance and driving ability, in a group of patients with cirrhosis and varying degrees of HE. Methods A total of 145 patients (120 males, 59 ± 10 years, model for end-stage liver disease [MELD] score 13 ± 5) underwent the PVT; a subgroup of 117 completed a driving questionnaire and a subgroup of 106 underwent the psychometric hepatic encephalopathy score (PHES) and an electroencephalogram (EEG), based on which, plus a clinical evaluation, they were classed as being unimpaired (n = 51), or as having minimal (n = 35), or mild overt HE (n = 20). All patients were followed up for an average of 13 ± 5 months in relation to the occurrence of accidents and/or traffic offences, HE-related hospitalisations and death. Sixty-six healthy volunteers evenly distributed by sex, age and education served as a reference cohort for the PVT. Results Patients showed worse PVT performance compared with healthy volunteers, and PVT indices significantly correlated with MELD, ammonia levels, PHES and the EEG results. Significant associations were observed between neuropsychiatric performance/PVT indices and licence/driving status. PVT, PHES and EEG results all predicted HE-related hospitalisations and/or death over the follow-up period; none predicted accidents or traffic offences. However, individuals with the slowest reaction times and most lapses on the PVT were often not driving despite having a licence. When patients who had stopped driving for HE-related reasons (n = 6) were modelled as having an accident or fine over the subsequent 6 and 12 months, PVT was a predictor of accidents and traffic offences, even after correction for MELD and age. Conclusions The PVT is worthy of further study for the purposes of both HE and driving ability assessment. Lay summary Hepatic encephalopathy (HE) is a complication of advanced liver disease that can manifest as excessive sleepiness. Some patients with HE have been shown to have difficulty driving. Herein, we used a test called the Psychomotor Vigilance Task (PVT), which measures sleepiness and can also be used to assess driving competence. We showed that PVT performance is fairly stable in healthy individuals. We also showed that PVT performance parallels performance in tests which are commonly used in cirrhotic patients to measure HE. We suggest that this test is helpful in quantifying HE and identifying dangerous drivers among patients with cirrhosis. [ABSTRACT FROM AUTHOR]

Abstract: Wilson''s disease is a genetic disorder characterized by accumulation of copper in many organs and tissues. Phenotypic manifestations are wide-ranging from neuropsychiatric disorders, to severe liver disease requiring liver transplantation. Clinical presentation is not often related to the genetic defect and siblings may have different type of disease. Liver transplantation is indicated for all patients with Wilson''s disease and decompensated liver cirrhosis unresponsive to medical therapy, but its efficacy in resolving the neurological symptoms is still controversial, because as far now, very different outcomes have been reported. We describe here on the exceptional case of two homozygotic twins, both with liver cirrhosis due to Wilson''s disease, one of them with severe neuropsychiatric involvement, who both underwent liver transplantation and subsequently had very different outcome despite same genetic background. The presence of neurological clinical manifestations in Wilson''s disease should recommend caution indicating liver transplantation, because irreversible brain damage may exist. [Copyright &y& Elsevier]

Alpha1-antitrypsin (α1-AT) deficiency is the most common genetic cause of liver disease in infants and children. The major clinical manifestations include liver disease (primarily in children) and emphysema in adults. For patients who progress to cirrhosis and liver failure, liver transplantation provides a metabolic cure for the deficiency and presumably prevents the associated complications. Several case reports in the pediatric literature describe glomerulonephritis in the setting of severe α1-AT deficiency, but this association is less well documented in adults. End-stage chronic kidney disease is a rare finding in the literature and kidney transplantation is the treatment of choice. We report on a 15-year-old boy with α1-AT deficiency and consequent end-stage liver disease and membranoproliferative glomerulonephritis rapidly progressing to renal failure, who successfully underwent combined liver-kidney transplantation. [Copyright &y& Elsevier]

A letter to the editor is presented which discusses the study on the impact of hepatitis C virus (HCV) in patients with liver disease and who undergo kidney transplantation (KT).