End-stage Liver Failure Research Articles

Recent solid-phase microextraction-based analytical approaches for the profiling of biliary bile acids in pre-transplant assessments of liver grafts subjected to normothermic ex vivo liver perfusion

BackgroundLiver transplantation is the definitive treatment for end-stage liver failure, but the scarcity of donor organs remains a significant challenge. Leveraging organs from extended criteria donors (ECD) offers a potential avenue to address worldwide shortages, though these organs are more susceptible to post-reperfusion injury. This study explores the use of normothermic ex vivo liver perfusion (NEVLP) as a method for organ preservation – an approach that sustains liver metabolism and facilitates pre-transplant assessments of organ viability via bile analysis. The focal point of this study revolves on the development of analytical methods for determining the bile acid profile throughout the peritransplantation period as a potential indicator of liver function and viability. ResultsThe study optimized and validated a high-throughput analytical method to quantify selected bile acids in bile samples using a thin-film microextraction-liquid chromatography-mass spectrometry (TFME-LC-MS) platform. Furthermore, it introduced a solid-phase microextraction-microfluidic open interface-mass spectrometry (SPME-MOI-MS) method for rapid direct analysis of bile acid isobar groups. In the animal study, discernible variations in the concentrations of specific bile acids were observed between donors after circulatory death (DCD) and heart-beating donors (HBD), particularly following normothermic perfusion and reperfusion. Noteworthy fluctuations in individual bile acid concentrations were observed throughout the entire organ transplantation process, with taurocholic acid (TCA), glycocholic acid (GCA), and glycochenodeoxycholic acid (GCDCA) emerging as promising indicators of organ quality. The efficacy of the SPME-MOI-MS platform in corroborating these trends highlights its potential for real-time bile acid analysis during liver transplantation procedures. SignificanceOur findings underscore the efficacy of NEVLP in tandem with advanced bile acid analysis methods as a reliable strategy for pre-transplant assessments of organ viability, potentially increasing the use of ECD organs and reducing organ shortages. The ability to monitor bile acid profiles in real-time provides crucial insights into liver function and ischemic injury, making significant strides in improving transplant outcomes and patient survival rates.

Understudied targets of the ischemia-reperfusion injury pathogenesis in liver transplantation

Background. Liver transplantation is currently the most effective method to treat diseases with end-stage liver failure. Complications are most often associated with the initially severe patient condition, imperfect organ preservation methods, the surgical management per se, and immune system incompetence. The most common complications of transplantation include ischemic reperfusion injury, which occurs to some or another extent in each transplanted organ and worsens the course of the postoperative period. The process is based on complex pathophysiological mechanisms of cell damage due to ischemia and inflammation caused by reperfusion.Objective. To summarize current data on the mechanisms of the ischemic reperfusion injury development in liver transplantation and to find the ways to reduce adverse effects.Material and methods. The analysis of data from foreign and homeland experimental and clinical studies on the pathogenesis of ischemic reperfusion injury in liver transplantation has been performed. The search for literature data was carried out in international databases (PubMed/MedLine, ResearchGate, as well as in the scientific electronic library of Russia (eLibrary.RU) for the period from 2020-2024.Conclusion. The analyzed publications have provided various algorithms for the preservation of donor organs, including those using machine perfusion.

Alcoholgeassocieerde hepatitis: geschikt voor transplantatie?

Alcohol-associated hepatitis: fit for transplant? Alcohol-associated hepatitis is one of the most severe stages of end-stage liver failure. In patients not responding to corticosteroids or when this medication is contraindicated, an early liver transplantation is the last treatment option. This article discusses the transplant process and various topics of controversy, such as relapse, outcome, ethics and organ scarcity, with the aim of determining whether these patients are good transplant candidates. This narrative review is based on 30 sources from various databases. Patients with alcohol-associated hepatitis not responding to corticosteroids have a high short-term mortality, which often makes a rapid intervention with an early liver transplantation the only option. An abstinence period of 6 months is therefore not possible in this population. The outcome of alcohol-associated hepatitis after the transplantation is similar to that of end-stage alcohol-associated liver disease. Only a small proportion of the patients with severe alcohol-associated hepatitis relapses after the transplantation, figures corresponding to those of alcoholic liver disease. The literature shows that, according to the principles of medical ethics, severe alcohol-associated hepatitis is a good indication for a liver transplantation, even in the context of the current organ shortage. The good outcome, low recurrence rates and high urgency and utility are the main reasons.

O180: An In Vitro Cell Model to Assess the Effects of Complement Inhibition on Ischemia-Reperfusion Injury in Cholangiocytes

Abstract Background Liver transplantation is the definitive procedure for end-stage liver failure but is limited by a shortage of viable donor organs. IRI is an unavoidable consequence of transplantation, triggering damage via several pathways, including complement activation. Development of an in vitro cell model of IRI with addition of complement allows analysis of cholangiocyte cellular stress response and whether this response can be attenuated by eculizumab, a complement inhibitor. Methods H69 cholangiocytes were subject to anoxic incubation for 4 hours and subsequent normoxia for 24 hours, before addition of complement to the system. Complement was provided from perfusate taken from liver normothermic machine perfusion (NMP). Analysis of cellular response was then carried out at different stages of simulated IRI. Results Eculizumab-treated perfusate significantly increased cell proliferation compared to untreated perfusate (p<0.0001). Addition of complement to the model increased cellular oxidative stress and inflammation. Eculizumab-treated perfusate significantly decreased production of GDF15 (p<0.0001), an oxidative stress marker, in cholangiocytes. Despite a significant increase, compared to the normoxic control, IL-10 and IL-8 production showed no significant difference between cells treated with control NMP perfusate or eculizumab-treated perfusate. VEGF gene expression was upregulated in the context of eculizumab-treated perfusate. Conclusion The in vitro model successfully simulates IRI and addition of perfusate leads to increased production of markers of inflammation and oxidative stress. Complement-depleted perfusate significantly reduced GDF15 production, suggesting amelioration of cellular oxidative stress, by eculizumab; however, we cannot conclude with the current data that complement-depleted perfusate attenuates the effects of IRI in this model.

Modification of Preservative Fluids with Antioxidants in Terms of Their Efficacy in Liver Protection before Transplantation.

Transplantation is currently the only effective treatment for patients with end-stage liver failure. In recent years, many advanced studies have been conducted to improve the efficiency of organ preservation techniques. Modifying the composition of the preservation fluids currently used may improve graft function and increase the likelihood of transplantation success. The modified fluid is expected to extend the period of safe liver storage in the peri-transplantation period and to increase the pool of organs for transplantation with livers from marginal donors. This paper provides a literature review of the effects of antioxidants on the efficacy of liver preservation fluids. Medline (PubMed), Scopus, and Cochrane Library databases were searched using a combination of MeSH terms: "liver preservation", "transplantation", "preservation solution", "antioxidant", "cold storage", "mechanical perfusion", "oxidative stress", "ischemia-reperfusion injury". Studies published up to December 2023 were included in the analysis, with a focus on publications from the last 30 years. A total of 45 studies met the inclusion criteria. The chemical compounds analyzed showed mostly bioprotective effects on hepatocytes, including but not limited to multifactorial antioxidant and free radical protective effects. It should be noted that most of the information cited is from reports of studies conducted in animal models, most of them in rodents.

Alcohol Relapse After Early Liver Transplantation in Patients With Alcoholic Liver Disease: A Meta-Analysis.

Alcohol use disorder (AUD) is a significant source of end-stage liver disease and liver failure and an indication for liver transplant (LT). Historically, LT for alcoholic liver disease (ALD) required 6 months of alcohol abstinence. Recently, it has been demonstrated that early LT (< 6 months of abstinence) in strictly selected group of patients provides survival benefit while keeping the relapse to harmful drinking at acceptable levels. This practice has been reflected in the Dallas consensus, but more data are needed to appropriately risk stratify the patient from the perspective of return to harmful alcohol drinking post-transplant. This "6-month rule" has been highly debated and recent data demonstrated that the duration of pre-transplant sobriety is not related with an increased risk of relapse to alcohol post-transplant. We performed a meta-analysis to compare the rate of alcohol relapse in individuals having standard vs. early LT. MEDLINE and SCOPUS were searched for randomized controlled trials (RCTs), observational studies, and case-control studies from their inception through June 2022. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMSA) 2009 checklist guidelines were followed for this meta-analysis. Studies comparing post-transplant outcomes, such as alcohol relapse, in individuals following standard vs. early LT, were included. Reviews, case studies, conference abstracts, clinical trials with only an abstract, and studies with inadequate data for extraction were all disqualified. The data were retrieved, gathered, and examined. The random effects model was used to generate forest plots. For the analysis, a P-value of 0.05 was considered significant. Thirty-four studies were discovered in the initial search. Three studies were included in this systematic review and meta-analysis incorporating 367 patients. Mean age was 51.7 years. Out of 367 patients, 173 (47%) underwent early LT. Out of three studies included, one study demonstrated decreased probability of alcohol relapse in patients undergoing early LT, whereas the other two showed the opposite result. All of the included studies were analyzed and had minimal risk of bias. Pooled analysis demonstrates that the difference in alcohol relapse between early vs. standard LT was insignificant (odds ratio: 1.24, 95% confidence interval: 0.75 - 2.06, P = 0.40). Our results show that early LT is not associated with increased risk of alcohol relapse post-transplant when compared with a mandatory 6-month abstinence period. Hence, individuals with ALD should not be categorically rejected from LT merely on the criteria of 6 months of abstinence. Other selection criteria based on the need and post-transplant outcomes should be utilized.

Multidrug-Resistant Infections After Liver Transplantation, Etiology and Risk Factors: A Single-Center Experience.

Patients undergoing liver transplant are at an increased risk of morbidity and mortality due to the development of infections. We aimed to evaluate the risk factors affecting the incidence of infectious diseases after liver transplant and to present the epidemiological data. We investigated patients aged ≥18 years who underwent liver transplant between 2012 and 2020 at our center. We collected infections, causative microorganisms, and antibacterial resistance patterns seen during the first 6 months posttransplant. Risk factors affecting the development of infectious diseases were also analyzed and evaluated. Of 112 patients included in our study, 76 (67.9%) were men, and the median age was 50 years (range, 20-66 years). Within month 1 and month 6 after transplant, at least 1 episode of infection occurred in 67 (59.8%) and 80 (71.4%) patients, respectively. Bacterial infections were the most common type (n = 78, 95.1%), followed by fungal (n = 2, 2.4%) and viral (n = 2, 2.4%) infections. The rate of multidrug resistance in bacterial infections was high (n = 38, 52.7%) and was also a risk factor for mortality in the first 6 months after transplant (P < .001). Pretransplant values of international normalized ratio, creatinine, bilirubin, and posttransplant intensive care unit stay, as well as the presence of encephalopathy, were shown to increase the risk of infection after transplant. Multidrug-resistant bacterial infections are a significant risk factor for mortality in liver transplant patients. Many risk factors that contribute to the development of infections aftertransplant have been included in prognostic scoring systems of liver failure. Consequently, the severity of end-stage liver failure is directly related to the risk of posttransplant infections.

Comprehensive research progress in stem cell therapy

Stem cell therapy is increasingly recognized as an innovative and transformative approach in the field of medicine, with the potential to address tissue damage and manage intricate medical conditions. The utilization of induced pluripotent stem cells (iPSCs) presents a potential avenue for cardiac regeneration in the context of cardiovascular ailments, such as myocardial infarctions. Liver regeneration techniques utilizing mesenchymal stem cells (MSCs) are being offered as potential solutions for end-stage liver failure. Furthermore, stem cell therapy is regarded as a promising intervention for neurodegenerative disorders and ocular conditions, with disease-specific induced pluripotent stem cells (iPSCs) emerging as a frontrunner in prospective therapeutic approaches. The objective of this study is to investigate the advancements made in stem cell therapy research for the diseases mentioned above. It will involve a comprehensive analysis of the mechanisms and principles underlying stem cell treatment in these areas, as well as an examination of the factors that impede the progress of stem cell therapy. Additionally, this paper will offer insights into potential future directions for development in this field.

The incidence of coronary artery disease after liver transplant: a meta-analysis

Abstract Purpose to investigate the incidence of coronary artery disease (CAD) events after liver transplant. Background Liver transplant (LT) can cure end-stage liver failure. CAD is a known complication after LT surgery. The incidence of CAD after LT is not well-established on short- and long-term perspectives. Methods We performed data searches in the PubMed till December 31, 2022. Inclusion criteria were observational trials evaluating new events of CAD in LT patients. Exclusion criteria were lack of follow-up CAD events after LT. Our primary outcome was the composite incidence of new myocardial infarctions (MIs), revascularisation due to CAD, and angina. The incidence of CAD was calculated through a generalised mixed effect meta-analysis. Sensitivity analyses were the incidence of MI, distinction of the short-term(≤12 months) and long-term(&amp;gt;12 months) incidences rates(new cases/months) of CAD, and univariate meta-regressions of study baseline characteristics and the CAD incidence. Results A total of 426 studies were retreated from PubMed (Figure 1). Of these, 23 studies were eligible for the meta-analysis. Age of patients ranged from 50 to 67 years. Female participants differed between 20 to 42%. CAD was prevalent in 1 to 60% before liver transplant. The incidence of CAD was 3% (95% CI, 2 to 5%). The incidence of MI was 1% (95% CI, 1 to 3%). The incidence rate was 4.40 (95% CI, 1.74 to 11.15) for follow-ups ≤ 12 months as compared to 0.22 (95% CI, 0.13 to 0.37) for follow-ups &amp;gt; 12 months (Figure 2). Meta-regressions showed prevalent CAD and number of study particants to be significantly associated with higher versus lower CAD incidence after LT (P = 0.03 &amp; P &amp;lt; 0.001). Conclusion The CAD incidence after LT was 3%. Despite high heterogeneity among studies, existing CAD before LT is a signifant risk factor for new CAD events. Incidence rates showed the CAD to be higher close to LT surgery.Figure 1:Flow chartFigure 2:incidence rates of CAD

High Density Lipoprotein Subfraction Changes in End Stage Liver Failure

BACKGROUND: This work was designed to ascertain high-density lipoprotein (HDL) subfractions and HDL-related enzyme alterations in end stage liver failure (ESLF). METHODS: Twenty patients with ESLF and twenty control subjects (liver donors) were chosen for the study. Before the transplant, serum samples from each patient and control were evaluated. Continuous disc polyacrylamide gel electrophoresis was performed to determine HDL subfraction changes and ELISA was carried out to determine serum levels of lecithin–cholesterol acyltransferase (LCAT), apolipoprotein A-1 (ApoA-I) and cholesteryl ester transfer protein (CETP). RESULTS: Liver failure patients had significantly higher levels of triglycerides (TG) and very low-density lipoprotein (VLDL) compared to healthy donors. Additionally, these patients showed significant increases in levels of aspartate aminotransaminase (AST), alkaline phosphatase (ALP), alanine aminotransaminase (ALT), and blood urea nitrogen (BUN), while albumin was notably lower compared to controls. Even though HDL cholesterol concentrations were not considerably altered between the two groups, ESLF patients had a marked raise in the HDL-large subfraction and a significant decline in the HDL-small subfraction in contrast to controls. Moreover, liver failure patients had considerably lower serum ApoA1 levels compared to healthy controls, but there was no significant difference in LCAT and CETP levels between the two groups. CONCLUSION: HDL subfraction profile can distinguish between healthy donors and liver failure patients. The results also indicate that levels of ApoA-1, which performs a crucial function in HDL metabolism, are lower in ESLF. This decrease in HDL-small subfractions may be due to impaired anabolism resulting from hepatic failure.

Biliary atresia: The profile, management and outcome of patients treated at a tertiary hospital in central South Africa

Background. Biliary atresia (BA) is an obstructive inflammatory disease of the bile ducts. Without intervention, the disease rapidly progresses to liver cirrhosis and fibrosis, with end-stage liver failure and death occurring within the first 3 years of life. It is the most common indication for liver transplantation (LT) in the paediatric population. The management of BA in South Africa (SA) faces multiple challenges, such as late referrals and socioeconomic burdens, with suboptimal outcomes. Objectives. To determine risk factors and shortcomings that are detrimental to the outcome of the paediatric patient population by reviewing the profile, management and outcome of patients with BA treated at Universitas Academic Hospital Complex (UAHC), Bloemfontein, SA. Methods. This was a retrospective analytical record review of all patients diagnosed with BA and treated at UAHC from 1 January 2009 to 31 December 2019. Results. In total, 67 patients were included; 74.6% were female, and 86.6% were black Africans. Most (62.7%) had isolated BA. A Kasai portoenterostomy (KPE) was performed in 32 patients (47.8%). Of 5 patients referred for LT evaluation, 2 received a transplant. Of 55 patients with known outcomes, 5.5% (n=3) survived and 94.5% (n=52) died after receiving a KPE or palliative treatment. Of the 3 patients who were alive at the end of the study period, 1 had a KPE and 2 had LTs. Conclusion. Late presentation, cholangitis and cessation of bile flow after an initial successful KPE, and socioeconomic challenges are issues of concern and had a detrimental influence on the outcome of BA in our study population. Implementing screening measures and education programmes at the primary healthcare level is essential to diagnose and refer BA patients timeously. Establishing support systems to assist socioeconomically disadvantaged patients will enable them to qualify for LT.

Empagliflozin suppresses hedgehog pathway, alleviates ER stress, and ameliorates hepatic fibrosis in rats

Worldwide mortality from hepatic fibrosis remains high, due to hepatocellular carcinoma and end stage liver failure. The progressive nature of hepatic fibrosis from inflammation to cicatrized tissues warrants subtle intervention with pharmacological agents that hold potential. Empagliflozin (Empa), a novel hypoglycemic drug with antioxidant and anti-inflammatory properties, has lately been proposed to have additional antifibrotic activities. In the current study, we examined the antifibrotic effect of the Empa through modulating the activity of hepatic stellate cells by hedgehog (Hh) pathway. We also assessed the markers of inflammatory response and endoplasmic reticulum (ER) stress. Male Albino rats were treated with either CCl4 (0.4 mg/kg twice/week) and/or Empa (10 mg/kg/day) for eight weeks. In this study, CCl4 rats had active Hh signaling as indicated by overexpression of Patched 1, Smoothened and Glioblastoma-2. CCl4 induced ER stress as CHOP expression was upregulated and ERAD was downregulated. CCl4-induced inflammatory response was demonstrated through increased levels of TNF-α, IL-6 and mRNA levels of IL-17 while undetectable expression of IL-10. Conversely, Empa elicited immunosuppression, suppressed the expression of Hh markers, and reversed markers of ER stress. In conclusion, Empa suppressed CCl4-induced Hh signaling and proinflammatory response, meanwhile embraced ER stress in the hepatic tissues, altogether provided hepatoprotection.

Development of VRE meningitis due to haematogenous spread while on high-dose daptomycin therapy.

Vancomycin-resistant Enterococcus faecium (VRE) meningitis accounts for only 0.3%-4.0% of bacterial meningitis cases and typically occurs following neurosurgical intervention. We describe a rare case of a patient without neurological devices in situ or a recent neurological procedure who developed VRE meningitis via haematogenous spread. Optimal treatment for VRE meningitis is unknown. A 67-year-old male with end-stage liver failure underwent liver transplantation complicated by VRE bacteraemia and subsequently developed VRE meningitis while on high-dose daptomycin therapy (12 mg/kg/day). Due to clinical and microbiological failure with daptomycin, he was switched to linezolid and symptoms resolved rapidly. He completed 2 weeks of linezolid, fully recovered, and continued to do well without complications at the 5 month follow-up. This case highlights the severity of VRE infections in solid organ transplant recipients and raises concerns about daptomycin penetration into the CNS. Linezolid could be considered the preferred treatment for VRE CNS infections rather than high-dose daptomycin.

Short-Term and Long-Term Effects of Ischemic Conditioning on Liver Transplantation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Although liver transplantation (LT) is one of the definitive treatments for patients with end-stage liver failure, it inevitably results in ischemic reperfusion injury. It is known that prognosis is improved when temporary ischemic conditioning (IC) is applied to patients with ischemic reperfusion injury. The objective of this meta-analysis was to determine the short-term and long-term effects of IC on the clinical outcomes of LT recipients. Randomized controlled studies on IC in patients with LTs were included. Patients were compared between an IC group and a sham group. Studies were retrieved from PubMed, Embase, and Cochrane Library. The risk of bias was evaluated using RoB 2.0. Mortality, graft function, and major complications were synthesized using RevMan 5.4.1. Among 316 papers, 17 articles (1196 patients) were included. There was an insignificant increase in short-term mortality (risk ratio [RR]: 3.00, 95% CI: 0.32-28.14, P=.34). However, long-term mortality was lower in the IC group than in the sham group, but not significantly (RR: 0.75; 95% CI: 0.47-1.20, P=.23). Short-term graft function (acute graft rejection and primary graft non-function) was not improved by IC. One-year graft loss tended to show better results in the IC group (RR: 0.53, 95% CI: 0.26-1.07, P=.08). Ischemic conditioning did not have a beneficial effect on LT. Although long-term outcomes appear to be better in the IC group than in the sham group, further randomized controlled trials are needed.

Protein-S-100-beta is increased in patients with decompensated cirrhosis admitted to ICU

BackgroundHepatic encephalopathy (HE) is highly prevalent in patients with liver diseases. The pathophysiology of HE is centered on the synergic role of hyperammonemia and systemic inflammation. However, some data suggest altered functioning of the blood–brain barrier (BBB). Assessing BBB function is challenging in clinical practice and at the bedside. Protein-S-100 Beta (PS100-Beta) could be a useful peripheral marker of BBB permeability in HE. This study aimed to assess plasmatic PS100-Beta levels in a prospective cohort of patients admitted to the intensive care unit (ICU) with decompensated cirrhosis with and without overt HE. MethodsWe retrospectively evaluated a prospective cohort of cirrhotic patients admitted to the ICU from October 2013 to September 2015 that had an available plasmatic PS100-Beta measurement. Patients with previous neurological impairment or limitation of intensive or resuscitative measures were excluded. Overt HE was defined as West-Haven grades 2 to 4. The patients were compared to a control cohort of outpatient clinic cirrhotic and non-cirrhotic patients explored for isolated elevation of liver enzymes. After ICU discharge, the patients were followed for at least 3 months for the occurrence of overt HE. Adverse outcomes (liver transplantation or death) were collected. The ability of PS100-Beta – in combination with other factors – to predict overt HE was evaluated in a multivariate analysis using logistic regression. Likelihood ratios were used to determine the effects and calculate odds ratios (OR). Survival analysis was performed by using the Kaplan–Meier method and survival between groups was compared using a Log-rank test. ResultsA total of 194 ICU patients and 207 outpatients were included in the study. Increased levels of plasmatic PS100-Beta were detected in the ICU decompensated cirrhotic patients compared with the outpatients ([0.15±0.01] mg/L vs. [0.08±0] mg/L, P <0.001). ICU patients with overt HE had higher levels of PS100-Beta ([0.19±0.03] mg/L) compared with the ICU patients without overt HE ([0.13±0.01] mg/L) (P=0.003). PS100-Beta levels did not differ in outpatients with F 0–3 compared to F 4 fibrosis (P=0.670). PS100-Beta values were correlated with Child-Pugh score (P <0.001), Model for End-Stage Liver Disease (MELD) score (P=0.004), C-reactive protein (P <0.001), ammonemia (P <0.001), and chronic liver failure consortium (CLIF-C) organ failure (P <0.001) and CLIF-C acute-on-chronic (P=0.038) scores, but not with leukocytes (P=0.053), procalcitonin (PCT) (P=0.107), or the lymphocyte-to-neutrophil ratio in ICU patients (P=0.522). In a multivariate model including age, ammonemia, PS100-Beta, PCT, MELD, presence of transjugular portosystemic shunt, and sodium level, the diagnostic performance was 0.765 for the diagnosis of overt HE. Patients with a PS100-Beta level <0.12 mg/L had a better overall survival (P=0.019) and a better survival without liver transplantation (P=0.013). ConclusionsSerum levels of PS100-Beta are elevated in ICU patients with decompensated cirrhosis, and even more so in those displaying overt HE, and the levels are correlated with outcome. This suggests an increase in the permeability of the BBB in these patients.

Extracellular Vesicles as Therapeutic and Diagnostic Tools for Chronic Liver Diseases.

Chronic liver diseases can lead to fibrotic changes that may progress to the development of cirrhosis, which poses a significant risk for morbidity and increased mortality rates. Metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), and viral hepatitis are prevalent liver diseases that may lead to cirrhosis. The advanced stages of cirrhosis can be further complicated by cancer development or end-stage liver disease and liver failure. Hence, early detection and diagnosis of liver fibrosis is crucial for preventing the progression to cirrhosis and improving patient outcomes. Traditionally, invasive liver biopsy has been considered the gold standard for diagnosing and staging liver fibrosis. In the last decade, research has focused on non-invasive methods, known as liquid biopsies, which involve the identification of disease-specific biomarkers in human fluids, such as blood. Among these alternative approaches, extracellular vesicles (EVs) have emerged as promising diagnostic and therapeutic tools for various diseases, including chronic liver diseases. EVs are released from stressed or damaged cells and can be isolated and quantified. Moreover, EVs facilitate cell-to-cell communication by transporting various cargo, and they have shown the potential to reduce the expression of profibrogenic markers, making them appealing tools for novel anti-fibrotic treatments. This review focuses on the impact of EVs in chronic liver diseases and exploring their potential applications in innovative therapeutic and diagnostic approaches.

Baricitinib with cyclosporine eliminates acute graft rejection in fully mismatched skin and heart transplant models.

Solid organ transplant represents a potentially lifesaving procedure for patients suffering from end-stage heart, lung, liver, and kidney failure. However, rejection remains a significant source of morbidity and immunosuppressive medications have significant toxicities. Janus kinase (JAK) inhibitors are effective immunosuppressants in autoimmune diseases and graft versus host disease after allogeneic hematopoietic cell transplantation. Here we examine the role of JAK inhibition in preclinical fully major histocompatibility mismatched skin and heart allograft models. Baricitinib combined with cyclosporine A (CsA) preserved fully major histocompatibility mismatched skin grafts for the entirety of a 111-day experimental period. In baricitinib plus CsA treated mice, circulating CD4+T-bet+ T cells, CD8+T-bet+ T cells, and CD4+FOXP3+ regulatory T cells were reduced. Single cell RNA sequencing revealed a unique expression profile in immune cells in the skin of baricitinib plus CsA treated mice, including decreased inflammatory neutrophils and increased CCR2- macrophages. In a fully major histocompatibility mismatched mismatched heart allograft model, baricitinib plus CsA prevented graft rejection for the entire 28-day treatment period compared with 9 days in controls. Our findings establish that the combination of baricitinib and CsA prevents rejection in allogeneic skin and heart graft models and supports the study of JAK inhibitors in human solid organ transplantation.

Current Status of Living Donor Liver Transplantation: Impact, Advantages, and Challenges.

This review provides an overview of the current status of Living Donor Liver Transplant (LDLT). It discusses the impact of LDLT on waitlist and post-transplantation outcomes, highlighting the technical challenges and unique advantages of LDLT. Recent findings show that LDLT offers several theoretical advantages over deceased donor liver transplant, including shorter wait times, better graft quality, and improved post-transplant outcomes. Non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) are emerging as the leading indications for adult LDLT in the US. LDLT demonstrates comparable or better overall survival rates and organ-specific outcomes compared to deceased donor transplants. However, challenges exist, including donor and recipient risks such as biliary complications and small-for-size syndrome. Ongoing research focuses on refining surgical techniques, exploring minimally invasive approaches, utilizing predetermined donors to modulate the recipient's immune system, and ensuring ethical practices. LDLT is a valuable solution for patients with end-stage liver failure or disorders requiring transplantation. It offers advantages such as shorter wait times as well as improved waitlist and post-transplant outcomes. Continued research and advancements in LDLT will benefit patients in need of liver transplantation.

A Case Report of Triple Organ Transplantation From a Donor After Circulatory Death Using Thoraco-Abdominal Normothermic Regional Perfusion

Organ transplantation with donation after circulatory death can potentially increase the donor pool. Here, we report the rare case of triple-organ (heart/liver/kidney) transplantation from a donor after circulatory death using thoraco-abdominal normothermic regional perfusion. The recipient was a 61-year-old man with end-stage heart failure, liver failure, and kidney failure secondary to arrhythmogenic right ventricular dysplasia. He received a heart/liver/kidney transplantation from a donor after circulatory death. The course was complicated with primary graft dysfunction of the heart that resolved on postoperative day 3. The patient was discharged on postoperative day 39. He has no evidence for rejection on heart biopsy, and all 3 organs exhibit stable function. The use of donation after cardiac death donors greatly increases the donor pool and should be considered for patients requiring multiorgan transplantation. The use of thoraco-abdominal normothermic reperfusion is not only a feasible method for multiorgan procurement but also provides enhanced protection for all transplanted organs.

Mortality and Morbidity Among Adult Liver Retransplant Recipients.

Liver transplantation (LT) is life-saving procedure for patients with end-stage liver failure with up to 20% of patients suffering graft failure following primary transplantation. Retransplantation (ReLT) remains the only definitive treatment for irreversible graft failure. We aimed to explore the postoperative outcomes following liver ReLT. Patients who had received a liver transplant between 2003 and 2016 were retrospectively identified using the Scientific Registry of Transplant Recipients (SRTRs). Patients were stratified based on previous liver transplant history. The primary outcomes of this study were 5-year postoperative mortality, morbidity, and length of hospital stay following LT. 60,554 (96%) recipients were first LT recipients and 2524 (4%) were ReLT recipients. Compared with first LT, ReLT recipients had significantly higher rates of mortality (OR 1.93, 95%CI 1.76-2.12), overall morbidity (OR 1.80, 95%CI 1.65-1.96), and prolonged length of stay (OR 1.66, 95%CI 1.52-1.81) on multivariate analysis. Morbidity including cardiovascular (CVD) complications (OR 1.32, 95%CI 1.08-1.60), graft failure (OR 2.18, 95%CI 1.84-2.57), infection (OR 2.13, 95%CI 1.82-2.50), and hemorrhage (OR 2.67, 95%CI 2.00-3.61) were significantly greater in ReLT recipients. Compared to first LT, ReLT patients had a significant increase in overall 5-year mortality (p < 0.001), 5-year mortality due to CVD complications (p < 0.001), infection (p = 0.009), but not graft failure (p = 0.3543). ReLT is associated with higher rates of 5-year mortality, overall morbidity, CVD morbidity, infection, and graft failure. Higher 5-year mortality in ReLT is due to CVD and infections. These results could be used in preoperative patient assessment and prognostic counseling for ReLT.