Sex disparities in acute-on-chronic liver failure: From admission to the intensive care unit to liver transplantation.

Acute-on-chronic liver failure (ACLF) is a severe clinical syndrome characterized by acute liver decompensation in patients with chronic liver disease, marked by systemic inflammation and systemic organ failure. In this review, we discussed sex-related disparities in the incidence, prognosis, and access to liver transplantation (LT) for patients with ACLF, particularly during Intensive Care Unit (ICU) management. Some studies have suggested that ACLF is more prevalent among male patients admitted to the ICU, and they have higher mortality rates than females. Available prognostic scores, such as CLIF-C or TAM-score, lack sex-specific adjustments. Sarcopenia seems to enhance the accuracy of these scores though this is observed only in male individuals. LT is the only effective treatment for patients with ACLF grade 2-3 who do not respond to medical therapies. Sex-related disparities occur in both access to LT and post-transplant outcomes, although the influence of sex on the prevalence, clinical course, and listing for LT in ACLF remains largely undetermined. A sex-orientated analysis of ICU outcomes in ACLF would facilitate the development of sex-orientated management strategies, thereby improving patients' outcomes.

Frailty and sarcopenia in patients with cirrhosis awaiting liver transplantation: evidence from a single-centre, prospective cohort study.

Sarcopenia and frailty are common complications in patients with cirrhosis evaluated for liver transplantation (LT). Although the negative impact of sarcopenia on patient's outcome has been well studied, the prognostic role of frailty is not as clear. We assessed the prevalence of sarcopenia and frailty and the clinical impact of frailty in a prospective cohort of cirrhosis patients with and without hepatocellular carcinoma (HCC) listed for LT. Patients with cirrhosis were prospectively recruited at the time of admission into the waiting list. Clinical and lab values were collected. Physical frailty was assessed by liver frailty index (LFI) and patients were categorized into robust (< 3.2); pre-frail (between 3.2 and 4.5), and frail (> 4.5). Skeletal muscle mass was evaluated via skeletal muscle index (SMI) obtained from last CT scan before LT; sarcopenia was defined by SMI < 50 cm2/m2 in males and < 39 cm2/m2 in females. 105 patients were included, of which 42 (40%) had hepatocellular carcinoma (HCC). In patients without HCC (63.5% males, median age 61 years), 36.5% were frail, 50.8% were pre-frail and 12.7% were robust. Frail patients were older than non-frail patients (63 vs. 56; p = 0.008) and had more severe liver disease (Child C: 65% vs. 37.5%; p = 0.02). Prevalence of sarcopenia in patients without HCC was 63%, with similar value of median SMI between frail and not frail patients (p = 0.454). Patients with HCC (78.6% males, 65 years old) were 21.4% frail, 61.9% pre-frail, and 16.7% robust. Frail patients had more severe liver disease (Child C: 77% vs. 18.2%; p = 0.004), whereas age was comparable to non-frail patients; among patients without HCC, during a median follow-up of 263 days, 17% died (of which 72% were frail) and 10 patients were delisted due to clinical improvement (none of whom were frail). Among those with HCC, during a median follow-up of 289 days, 4 (9%) patients died of which 50% were frail. Frailty and sarcopenia are common complications in patients with cirrhosis awaiting LT. Frailty appears to be associated with an increased risk of mortality during wait-list time especially in those with decompensated cirrhosis. At univariate analysis Meld score, Child score and presence of frailty were found to be associated with shorter survival, however, at multivariate analysis presence of frailty and Child C vs. A/B were the only independent predictor of death. Larger cohorts are required to confirm these results.

The impact of stigma on quality of life and liver disease burden among patients with nonalcoholic fatty liver disease.

Background & Aims: Patients with nonalcoholic fatty liver disease (NAFLD)/metabolic dysfunction-associated steatotic liver disease (MASLD) face a multifaceted disease burden which includes impaired health-related quality of life (HRQL) and potential stigmatization. We aimed to assess the burden of liver disease in patients with NAFLD and the relationship between experience of stigma and HRQL. Methods: Members of the Global NASH Council created a survey about disease burden in NAFLD. Participants completed a 35-item questionnaire to assess liver disease burden (LDB) (seven domains), the 36-item CLDQ-NASH (six domains) survey to assess HRQL and reported their experience with stigmatization and discrimination. Results: A total of 2,117 patients with NAFLD from 24 countries completed the LDB survey (48% Middle East and North Africa, 18% Europe, 16% USA, 18% Asia) and 778 competed CLDQ-NASH. Of the study group, 9% reported stigma due to NAFLD and 26% due to obesity. Participants who reported stigmatization due to NAFLD had substantially lower CLDQ-NASH scores (all p <0.0001). In multivariate analyses, experience with stigmatization or discrimination due to NAFLD was the strongest independent predictor of lower HRQL scores (beta from -5% to -8% of score range size, p <0.02). Experience with stigmatization due to obesity was associated with lower Activity, Emotional Health, Fatigue, and Worry domain scores, and being uncomfortable with the term "fatty liver disease" with lower Emotional Health scores (all p <0.05). In addition to stigma, the greatest disease burden as assessed by LDB was related to patients' self-blame for their liver disease. Conclusions: Stigmatization of patients with NAFLD, whether it is caused by obesity or NAFLD, is strongly and independently associated with a substantial impairment of their HRQL. Self-blame is an important part of disease burden among patients with NAFLD. Impact and implications: Patients with nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), may experience impaired health-related quality of life and stigmatization. Using a specifically designed survey, we found that stigmatization of patients with NAFLD, whether it is caused by obesity or the liver disease per se, is strongly and independently associated with a substantial impairment of their quality of life. Physicians treating patients with NAFLD should be aware of the profound implications of stigma, the high prevalence of self-blame in the context of this disease burden, and that providers' perception may not adequately reflect patients' perspective and experience with the disease.

The impact of socioeconomic deprivation on liver transplantation.

Despite global expansion, social disparities impact all phases of liver transplantation, from patient referral to post-transplant care. In pediatric populations, socioeconomic deprivation is associated with delayed referral, higher waitlist mortality, and reduced access to living donor transplantation. Children from socially deprived communities are twice as much less adherent to immunosuppression and have up to a 32% increased incidence of graft failure. Similarly, adult patients from deprived areas and racial minorities have a higher risk of not initiating the transplant evaluation, lower rates of waitlisting, and a 6% higher risk of not being transplanted. Social deprivation is racially segregated, and Black recipients have an increased risk of post-transplant mortality by up to 21%. The mechanisms linking social deprivation to inferior outcomes are not entirely elucidated, and powered studies are still lacking. We offer a review of the most recent evidence linking social deprivation and post-liver transplant outcomes in pediatric and adult populations, as well as a literature-derived theoretical background model for future research on this topic.

Alcoholic Etiology, Severity of Liver Disease, and Post-Transplant Adherence Are Correlated with Worse Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) in Liver Transplant Candidates.

Introduction: Psychosocial pre-transplant evaluation in patients undergoing liver transplantation (LT) could help identify those patients at higher risk of pharmacological non-adherence, organ rejection, and mortality. The Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) is a validated tool for assessing LT candidates' psychosocial well-being. Data on the ability of the SIPAT evaluation to predict post-transplant outcomes are sparse. Material and Methods: clinical and psychosocial data from a sample of 134 candidates for LT were analyzed. Moreover, the association between pre-transplant psychosocial evaluation and post-transplant clinical outcomes, including organ rejection, mortality, and immunosuppressant drug adherence, was calculated. Results: At the pre-transplant evaluation, patients who showed high SIPAT scores (77, 57%) also had more liver disease assessed by model for end-stage liver disease (MELD; F = 5.04; p < 0.05), alcoholic etiology (F = 35.80; p < 0.001), encephalopathy (F = 5.02; p < 0.05), and portal hypertension (F = 7.45; p < 0.01). Of the 51 transplant patients, those who had a high pre-transplant SIPAT score showed lower post-transplant immunosuppressive adherence, linked to more frequent immunological events. Conclusions: Patients with an alcoholic etiology of liver disease and more severe liver dysfunction are likelier to not adhere to medical prescriptions following transplantation. Current data suggests that this specific group of patients could benefit from early psychological pre-habilitation before undergoing liver transplantation.

ERS Statement on Benign Pleural Effusions in Adults.

The incidence of non-malignant pleural effusions (NMPE) far outweighs that of malignant pleural effusions (MPE) and is estimated to be at least 3-fold higher. These so called "benign" effusions do not follow a "benign course" in many cases, with mortality rates matching and sometimes exceeding that of MPEs. In addition to the impact on patients, healthcare systems are significantly affected, with recent US epidemiological data demonstrating that 75% of resource allocation for pleural effusion management is spent on NMPEs (excluding empyema). Despite this significant burden of disease, and by existing at the junction of multiple medical specialties, reflecting a heterogenous constellation of medical conditions, NMPEs are rarely the focus of research or the subject of management guidelines. With this ERS Taskforce, we assembled a multi-specialty collaborative across eleven countries and three continents to provide a Statement based on systematic searches of the medical literature to highlight evidence in the management of the following clinical areas: a diagnostic approach to transudative effusions, heart failure, hepatic hydrothorax, end stage renal failure, benign asbestos related pleural effusion, post-surgical effusion and non-specific pleuritis.

Coagulation factor XI in cirrhosis does not predict thrombo-hemorrhagic complications and hepatic decompensation.

INTRODUCTION: Factor XI (FXI) is associated with thrombosis in patients without liver disease, but it alterations and prognostic value in cirrhosis are uncertain. PATIENTS AND METHODS: We studied a prospective cohort of cirrhosis patients determining FXI and its association with portal vein thrombosis (PVT), bleeding, and hepatic decompensation/ACLF during 1-year follow-up. Odds ratios (OR) and 95 % CIs were calculated using logistic regression. RESULTS: We included 183 patients (Child-Pugh [CP] A/B/C 57/59/57). FXI was reduced in cirrhosis, decreasing with CP stage (78 % [66-94] vs. 58 % [44-78] vs. 41 % [30-52] in CP A, B, and C, respectively; p < 0.001). FXI was correlated with MELD score (rho: -0.6, p < 0.001), INR (rho: -0.6, p < 0.001), and platelet count (rho: 0.4, p < 0.001). Sixteen patients (8.7 %) experienced PVT, which only predictor was baseline platelet count (OR: 0.94; CI95 %: 0.91-0.97, p < 0.001). Bleeding occurred in 7 patients (3.8 %). Cirrhosis severity, platelet count, fibrinogen, and FXI (60% vs. 78 %; p = 0.2) were comparable between bleeding and non-bleeding individuals. Finally, no association was found between FXI and hepatic decompensation/ACLF, which were predicted by lower albumin and platelet count, respectively. CONCLUSION: FXI seems not to be responsible for thrombosis and cirrhosis progression. The lack of association between low FXI and bleeding events, however, indirectly opens to future studies evaluating FXI inhibitors in cirrhosis.

Multidrug-resistant bacterial infections in the liver transplant setting.

Bacterial infections pose a life-threatening complication in patients with decompensated liver cirrhosis and acute-on-chronic liver failure. An increasing prevalence of infections caused by multidrug-resistant organisms (MDROs) has been observed in these patients, significantly impacting prognosis. A growing body of evidence has identified the most common risk factors for such infections, enabling the development of preventive strategies and therapeutic interventions. MDRO infections may also occur after liver transplantation (most commonly in the early post-operative phase), affecting both graft and patient survival. This review provides an overview of MDRO infections before and after liver transplantation, discussing epidemiological aspects, risk factors, prevention strategies, and novel therapeutic approaches. Furthermore, it examines the implications of MDRO infections in the context of prioritizing liver transplantation for the most severe patients, such as those with acute-on-chronic liver failure.

Recurrence of autoimmune liver diseases after liver transplantation: Review and expert opinion statement.

Autoimmune liver diseases (AILDs) constitute the fourth most common indication for liver transplantation (LT) across the world. In general, the outcomes after LT are acceptable; however, disease recurrence after LT is common for all AILD, which can negatively affect graft and overall survival. Several questions persist, including the risk factors associated with recurrent disease, optimal antirejection medications, strategies to reduce the risk of recurrence, and how to best incorporate these strategies into clinical practice. For that reason, we assembled an international group of experts to review evidence to address these outstanding questions regarding LT for AILD. Survival rates after LT are ~90% and 70% at 1 and 5 years, and recurrent disease occurs in 10%-50% of patients with AILD. In patients with disease recurrence, graft survival decreased by 18% and 28% and overall survival by 8% and 12% at 5 and 10 years after LT, respectively. Recurrent autoimmune hepatitis is associated with high aminotransferases and immunoglobulin G (IgG) before LT, lymphoplasmacytic infiltrates in the explants, and may be associated with the absence of steroids after LT. However, the efficiency and safety of triple immunosuppressive maintenance therapy is still debatable. Younger age at diagnosis with primary biliary cholangitis or LT is associated with primary biliary cholangitis recurrence. Preventive use of ursodeoxycholic acid reduces the risk of recurrence and has a benefit in graft and patient survival. Episodes of systemic inflammation, including T-cell-mediated rejection, active ulcerative colitis, and episodes of cholangitis, are associated with recurrent PSC. Recurrent disease for AILD is associated with worse graft and patient survival. Patients with autoimmune hepatitis could be considered for long-term low-dose predniso(lo)ne, whereas patients with primary biliary cholangitis should be placed on preventive ursodeoxycholic acid after LT. There are no specific treatments for PSC recurrence; however, adequate control of inflammatory bowel disease and optimal immunosuppression to avoid T-cell-mediated rejection should be encouraged.

Liver transplantation for Wilson disease: Current knowledge and future perspectives.

Liver transplantation currently represents a therapeutic option for patients with Wilson disease presenting with end-stage liver disease or acute liver failure. Indeed, it has been associated with excellent postoperative survival curves in view of young age at transplant and absence of recurrence. Attention has shifted over the past decades to a wise expansion of indications for liver transplantation. Evidence has emerged supporting the transplantation of carefully selected patients with primarily neuropsychiatric symptoms and compensated cirrhosis. The rationale behind this approach is the potential for surgery to improve copper homeostasis and consequently ameliorate neuropsychiatric symptoms. However, several questions remain unanswered, such as how to establish thresholds for assessing pretransplant neuropsychiatric impairment, how to standardize preoperative neurological assessments, and how to define postoperative outcomes for patients meeting these specific criteria. Furthermore, a disease-specific approach will be proposed both for the liver transplant evaluation of candidates with Wilson disease and for patient care during the transplant waiting period, highlighting the peculiarities of this systemic disease.

The Equitable Benefit Approach to guide the assessment of medical and psychosocial factors in liver transplant candidacy.

Lack of available organs poses a significant challenge in meeting the needs of patients with life-threatening liver disease who could benefit from liver transplantation (LT). Psychosocial vulnerability markers have been linked to post-transplant outcomes, raising questions about their use in patient selection. However, their incorporation into selection criteria raises concerns about health equity and potential discrimination. As a result, there is a pressing need to refine fair allocation systems that consider both clinical and psychosocial factors to ensure equitable access and optimize post-transplant outcomes. The Equitable Benefit Approach (EBA) proposed in this paper by the multidisciplinary group of clinical experts in LT from the Italian Society for the Study of the Liver seeks to address these concerns. It presents four procedural principles, the two allocative principles usually applied in transplantation (urgency and utility) and introduces a new one, the principle of health equity. The EBA aims to prioritize patients with the highest transplant benefit while addressing health inequalities. It emphasizes evidence-based decision-making and standardized assessment tools to reliably evaluate psychosocial risk factors. Implementing the EBA involves a multi-step process, including stakeholder engagement, prospective studies to validate its efficacy, development of institutional policies and algorithms, and ongoing monitoring and revision. By following these steps, health care providers can ensure that LT allocation decisions are transparent and responsive to evolving clinical and social contexts. Ultimately, the EBA should offer a comprehensive framework for fair patient selection in LT, considering both biomedical and psychosocial aspects.

Prognostic scores for ursodeoxycholic acid-treated patients predict graft loss and mortality in recurrent primary biliary cholangitis after liver transplantation.

BACKGROUND & AIMS: Recurrent primary biliary cholangitis (rPBC) develops in approximately 30% of patients and negatively impacts graft and overall patient survival after liver transplantation (LT). There is a lack of data regarding the response rate to ursodeoxycholic acid (UDCA) in rPBC. We evaluated a large, international, multi-center cohort to assess the performance of PBC scores in predicting the risk of graft and overall survival after LT in patients with rPBC. METHODS: A total of 332 patients with rPBC after LT were evaluated from 28 centers across Europe, North and South America. The median age at the time of rPBC was 58.0 years [IQR 53.2-62.6], and 298 patients (90%) were female. The biochemical response was measured with serum levels of alkaline phosphatase (ALP) and bilirubin, and Paris-2, GLOBE and UK-PBC scores at 1 year after UDCA initiation. RESULTS: During a median follow-up of 8.7 years [IQR 4.3-12.9] after rPBC diagnosis, 52 patients (16%) had graft loss and 103 (31%) died. After 1 year of UDCA initiation the histological stage at rPBC (hazard ratio [HR] 3.97, 95% CI 1.36-11.55, p = 0.01), use of prednisone (HR 3.18, 95% CI 1.04-9.73, p = 0.04), ALP xULN (HR 1.59, 95% CI 1.26-2.01, p <0.001), Paris-2 criteria (HR 4.14, 95% CI 1.57-10.92, p = 0.004), GLOBE score (HR 2.82, 95% CI 1.71-4.66, p <0.001), and the UK-PBC score (HR 1.06, 95% CI 1.03-1.09, p <0.001) were associated with graft survival in the multivariate analysis. Similar results were observed for overall survival. CONCLUSION: Patients with rPBC and disease activity, as indicated by standard PBC risk scores, have impaired outcomes, supporting efforts to treat recurrent disease in similar ways to pre-transplant PBC. IMPACT AND IMPLICATIONS: One in three people who undergo liver transplantation for primary biliary cholangitis develop recurrent disease in their new liver. Patients with recurrent primary biliary cholangitis and incomplete response to ursodeoxycholic acid, according to conventional prognostic scores, have worse clinical outcomes, with higher risk of graft loss and mortality in similar ways to the disease before liver transplantation. Our results supportsupport efforts to treat recurrent disease in similar ways to pre-transplant primary biliary cholangitis.

Risk Factors for Recurrence of Primary Sclerosing Cholangitis after Liver Transplantation: Single-Center Data.

BACKGROUND: Primary sclerosing cholangitis (PSC), comprising 5-15% of European liver transplantation (LT) cases, poses a significant challenge due to the risk of post-transplant disease recurrence (rPSC). This single-center study aimed to determine the rPSC rate and long-term post-LT outcomes in PSC patients and to identify potentially modifiable risk factors of rPSC. METHODS: All PSC patients receiving LT at Padua Hospital from 1993 to 2021 were included. Recipient data were collected pre-LT, at LT, and during the follow-up. Donor and LT features were recorded. The rPSC rate was assessed according to Mayo Clinic criteria. Patient and graft survival were reported. RESULTS: Thirty-three patients were included. The main indication of LT was decompensated cirrhosis (70%). Nine patients (27%) developed rPSC during a median follow-up of 59 months (45-72). A longer cold ischemia time (p = 0.026), donor female gender (p = 0.049), inflammatory bowel disease reactivation (IBD) post LT (p = 0.005) and hepaticojejunostomy (p = 0.019) were associated with a higher risk of rPSC. Graft and patient survival at 1, 5 and 10 years post LT, 94%, 86%, 74% and 97%, 89%, 77% respectively, were not affected by rPSC development. CONCLUSION: Specific donor and surgical features might increase the risk of rPSC. Identifying predictive factors for rPSC to prevent graft loss is challenging but could lead to a more personalized organ allocation and follow-up in PSC transplanted patients. IBD reactivation might have a pathogenic role in rPSC. In our single-center experience, rPSC did not affect patient and graft survival.

Evolution of Liver Transplantation Indications: Expanding Horizons.

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.

Workup and management of liver transplantation in alcohol-related liver disease.

Alcohol-related liver disease (ALD) represents the most common indication for liver transplantation (LT) worldwide. Outcomes of LT for ALD are comparable with those of LT for other etiologies; however, ALD is still considered a controversial indication for LT, mainly because it is considered a self-inflicted disease with a high risk of return to alcohol use after LT. Pre-LT evaluation criteria have changed over time, with a progressive re-evaluation of the required pre-transplant duration of abstinence. Despite the fact that some transplant programs still require 6 months of abstinence in order to consider a patient suitable for LT, there is increasing evidence that a pre-transplant abstinence period of <6 months can be considered for well-selected patients. Early LT for severe alcohol-related hepatitis that has not responded to medical therapy has been shown to be an effective therapeutic option with high survival benefit when performed within strict and well-recognized criteria. However, high variability in LT access exists for these patients due to the presence of social and medical stigma. A psycho-social assessment, together with an evaluation by an addiction specialist, should be mandatory in patients with ALD who are potential candidates for LT in order to assess the risk of post-transplant return to alcohol use and to ensure good long-term outcomes. Finally, before LT, attention should be paid to the presence of other potential comorbidities (i.e., cardiovascular and neurological diseases), which could represent a potential contraindication to LT. Similarly, after LT, patients should be adequately monitored for the development of cardiovascular events and screened for "de novo" tumors, although standardized protocols for this monitoring do not exist at this time.