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Background: 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., Methods: 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., Results: 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)., Conclusion: 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., Competing Interests: None to declare., (Copyright 2024, Zafar et al.)

Background: Liver transplant (LT) is a highly effective therapy for refractory severe alcohol-associated hepatitis (SAH), but optimal selection criteria remain unknown. We aim to evaluate the outcomes of patients who received LT for alcohol-associated liver disease at our center following the introduction of updated selection criteria, including the removal of the minimum sobriety requirement., Methods: Data were collected on all patients who underwent LT for alcohol-associated liver disease from January 1, 2018, to September 30, 2020. Patients were divided into SAH and cirrhosis cohorts based on disease phenotype., Results: One hundred twenty-three patients underwent LT for alcohol-associated liver disease, including 89 (72.4%) for cirrhosis and 34 (27.6%) for SAH. There was no difference in 1- (97.1 ± 2.9% vs. 97.7 ± 1.6%, p = 0.97) and 3-year (97.1 ± 2.9% vs. 92.4 ± 3.4%, p = 0.97) survival between SAH and cirrhosis cohorts. Return to alcohol use was more frequent in the SAH cohort at 1 year (29.4 ± 7.8% vs. 11.4 ± 3.4%, p = 0.005) and 3 years (45.1 ± 8.7% vs. 21.0 ± 6.2%, p = 0.005) including higher frequencies of both slips and problematic drinking. Unsuccessful alcohol use counseling (HR 3.42, 95% CI 1.12-10.5) and prior alcohol support meetings (HR 3.01, 95% CI 1.03-8.83) predicted a return to harmful alcohol use patterns in early LT recipients. Both duration of sobriety (c-statistic 0.32 (95% CI 0.34-0.43) and SALT score (c-statistic 0.47, 95% CI 0.34-0.60) were independently poor predictors of return to harmful drinking., Conclusion: Survival following LT was excellent in both SAH and cirrhosis cohorts. Higher rates of return to alcohol use highlight the importance of further individualized refinement of selection criteria and improved support following LT., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Here we present the case of a cystic fibrosis (CF) patient with preserved pulmonary function who developed acute liver failure requiring liver transplant following an episode of binge drinking and ingestion of a modest amount of acetaminophen. Cystic Fibrosis Liver Disease (CFLD) is the third most common cause of death among CF patients. The pathogenesis of CFLD is complex and still not fully understood. It is important that patients suffering from CF know about the possible dangers associated with acetaminophen and ethanol ingestion. Our case report highlights the need for more research that needs to be done to truly understand the underlying pathogenesis of CFLD and the significant risk factors that play a part in the development of acute liver failure in patients with CF.

Purpose of Review: Hepatocellular carcinoma (HCC) surveillance in patients with cirrhosis is associated with decreased mortality by enabling early tumor detection. However, the benefits of any cancer screening program must be considered in light of potential physical, financial, and psychological harms, as well as the risk of overdiagnosis. Herein, we summarize the potential harms of HCC surveillance., Recent Findings: To date, two retrospective studies have addressed physical harms of HCC surveillance. Based on these data, 15% to 28% of patients undergoing HCC surveillance experience physical harm including additional cross-sectional imaging or liver biopsy. Although psychological and financial harms have been reported for other cancers, there are currently limited data specific to HCC. An ongoing multi-center prospective study assessing all four types of harms should provide data in near future., Summary: HCC screening may prevent death by diagnosing tumors at an early stage, but limited sensitivity and specificity of screening tests can result in unintended harms. There is a need for further quality data evaluating both the benefits and harms of HCC surveillance., Competing Interests: Conflicts of Interest: Amit Singal has been on advisory boards and served as a consultant for Wako Diagnostics, Roche, Exact Sciences, Glycotest, Bayer, Eisai, BMS, and Exelixis. The other authors have no conflicts to report.

Excessive accumulation of lipids in the liver is crucial in the pathogenesis of alcoholic steatohepatitis and may be partly mediated by impaired degradation of lipid droplets by autophagy. The E3 ubiquitin ligase SMAD-specific E3 ubiquitin protein ligase 1 (SMURF1) regulates selective autophagy by ubiquitinating proteins on cargo destined for autophagic delivery to the lysosome for degradation. Here, we evaluated the role of SMURF1 in the regulation of hepatic lipid degradation in alcoholic steatohepatitis. In patients with severe alcoholic hepatitis, SMURF1 colocalized with lipid droplet membranes in liver explants. In a mouse model of alcoholic steatohepatitis, Smurf1 -/- mice fed an alcohol diet displayed increased hepatocyte accumulation of lipid droplets and triglycerides as well as more severe liver injury compared to wild-type mice. The increased severity of liver steatosis in alcohol-fed Smurf1 -/- mice was rescued by adeno-associated virus (AAV) serotype 8-mediated hepatic expression of wild-type Smurf1 protein but not by mutant Smurf1 proteins either lacking the catalytically active cysteine 699 required for ubiquitin transfer or the N-terminal C2 phospholipid membrane-binding domain. Conclusion: Smurf1 plays a protective role in the pathogenesis of alcoholic steatohepatitis through a mechanism that requires both its ubiquitin-ligase activity and C2 phospholipid-binding domains. These findings have implications for understanding the roles of ubiquitin ligases in fatty liver disease., (© 2019 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.)

Bile acids (BAs) activate various dedicated receptors, including the farnesoid X receptor (FXR) and the Takeda G protein-coupled receptor 5 (TGR5). The FXR agonist obeticholic acid (OCA) is licensed for the treatment of primary biliary cholangitis and has shown promising results in NASH patients, whereas TGR5 agonists target inflammation and metabolism. We hypothesized that FXR and/or TGR5 agonists may be therapeutic in early alcoholic liver disease (ALD) in mice, in which hepatic inflammation plays a major role. OCA, INT-777, and INT-767 are BA derivatives with selective agonist properties for FXR, TGR5, or both, respectively. These compounds were tested in two mouse models (3-day binge model and prolonged Lieber DeCarli diet for 12 days) of early ALD. Serum alanine aminotransferase and liver histology were used to assess liver injury, Oil Red O staining of liver sections to assess steatosis, and real-time polymerase chain reaction to assess changes in gene expression. In the ethanol binge model, treatment with OCA and INT-777 decreased hepatic macrovesicular steatosis and protected from ethanol-induced liver injury. After prolonged ethanol administration, mice treated with OCA, INT-767, or INT-777 showed decreased hepatic steatosis, associated with reduced liver fatty acid synthase protein expression, and protection from liver injury. Treatment with BA receptor agonists in both models of ethanol administration modulated lipogenic gene expression, and decreased liver interleukin-1β mRNA expression associated with increased ubiquitination of NLRP3 inflammasome through cyclic adenosine monophosphate-induced activation of protein kinase A. Conclusion: OCA, INT-767, or INT-777 administration is effective in reducing acute and chronic ethanol-induced steatosis and inflammation in mice, with varying degrees of efficacy depending on the duration of ethanol administration, indicating that both FXR and TGR5 activation can protect from liver injury in ALD models.

Background: Innate immunity plays a critical role in the development of alcohol-induced liver inflammation. Understanding the inter-relationship of signals from within and outside of the liver that trigger liver inflammation is pivotal for development of novel therapeutic targets of alcoholic liver disease (ALD)., Aim: The aim of this paper is to review recent advances in the field of alcohol-induced liver inflammation., Methods: A detailed literature review was performed using the PubMed database published between January 1980 and December 2016., Results: We provide an update on the role of intestinal microbiome, metabolome and the gut-liver axis in ALD, discuss the growing body of evidence on the diversity of liver macrophages and their differential contribution to alcohol-induced liver inflammation, and highlight the crucial role of inflammasomes in integration of inflammatory signals in ALD. Studies to date have identified a multitude of new therapeutic targets, some of which are currently being tested in patients with severe alcoholic hepatitis. These treatments aim to strengthen the intestinal barrier, ameliorate liver inflammation and augment hepatocyte regeneration., Conclusion: Given the complexity of inflammation in ALD, multiple pathobiological mechanisms may need to be targeted at the same time as it seems unlikely that there is a single dominant pathogenic pathway in ALD that would be easily targeted using a single target drug approach., Short Summary: Here, we focus on recent advances in immunopathogenesis of alcoholic liver disease (ALD), including gut-liver axis, hepatic macrophage activation, sterile inflammation and synergy between bacterial and sterile signals. We propose a multiple parallel hit model of inflammation in ALD and discuss its implications for clinical trials in alcoholic hepatitis., (© The Author 2017. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

Background & Aims: Inflammation and impaired hepatocyte regeneration contribute to liver failure in alcoholic hepatitis (AH). Interleukin (IL)-1 is a key inflammatory cytokine in the pathobiology of AH. The role of IL-1 in liver regeneration in the recovery phase of alcohol-induced liver injury is unknown., Methods: In this study, we tested IL-1 receptor antagonist to block IL-1 signalling in a mouse model of acute-on-chronic liver injury on liver inflammation and hepatocyte regeneration in AH., Results: We observed that inhibition of IL-1 signalling decreased liver inflammation and neutrophil infiltration, and resulted in enhanced regeneration of hepatocytes and increased rate of recovery from liver injury in AH., Conclusion: Our novel findings suggest that IL-1 drives sustained liver inflammation and impaired hepatocyte regeneration even after cessation of ethanol exposure., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Fibrosis, driven by inflammation, marks the transition from benign to progressive stages of chronic liver diseases. Although inflammation promotes fibrogenesis, it is not known whether other events, such as hepatocyte death, are required for the development of fibrosis. Interferon regulatory factor 3 (IRF3) regulates hepatocyte apoptosis and production of type I IFNs. In the liver, IRF3 is activated via Toll-like receptor 4 (TLR4) signaling or the endoplasmic reticulum (ER) adapter, stimulator of interferon genes (STING). We hypothesized that IRF3-mediated hepatocyte death is an independent determinant of chemically induced liver fibrogenesis. To test this, we performed acute or chronic CCl 4 administration to WT and IRF3-, Toll/Interleukin-1R (TIR) domain-containing adapter-inducing interferon-β (TRIF)-, TRIF-related adaptor molecule (TRAM)-, and STING-deficient mice. We report that acute CCl 4 administration to WT mice resulted in early ER stress, activation of IRF3, and type I IFNs, followed by hepatocyte apoptosis and liver injury, accompanied by liver fibrosis upon repeated administration of CCl 4 Deficiency of IRF3 or STING prevented hepatocyte death and fibrosis both in acute or chronic CCl 4 In contrast, mice deficient in type I IFN receptors or in TLR4 signaling adaptors, TRAM or TRIF, upstream of IRF3, were not protected from hepatocyte death and/or fibrosis, suggesting that the pro-apoptotic role of IRF3 is independent of TLR signaling in fibrosis. Hepatocyte death is required for liver fibrosis with causal involvement of STING and IRF3. Thus, our results identify that IRF3, by its association with STING in the presence of ER stress, couples hepatocyte apoptosis with liver fibrosis and indicate that innate immune signaling regulates outcomes of liver fibrosis via modulation of hepatocyte death in the liver., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

Aortoesophageal fistula is a rare and serious condition that carries a high mortality rate. We present a case of overt gastrointestinal bleeding from an aortoesophageal fistula in a patient with chronic infection of an endovascular prosthesis with Coxiella burnetii.

Background & Aims: The inflammasome is a well-characterized inducer of inflammation in alcoholic steatohepatitis (ASH). Inflammasome activation requires two signals for mature interleukin (IL)-1β production. Here we asked whether metabolic danger signals trigger inflammasome activation in ASH., Methods: Wild-type mice, ATP receptor 2x7 (P2rx7)-KO mice, or mice overexpressing uricase were fed Lieber-DeCarli ethanol or control diet. We also implemented a pharmacological approach in which mice were treated with probenecid or allopurinol., Results: The sterile danger signals, ATP and uric acid, were increased in the serum and liver of alcohol-fed mice. Depletion of uric acid or ATP, or lack of ATP signaling attenuated ASH and prevented inflammasome activation and its major downstream cytokine, IL-1β. Pharmacological depletion of uric acid with allopurinol provided significant protection from alcohol-induced inflammatory response, steatosis and liver damage, and additional protection was achieved in mice treated with probenecid, which depletes uric acid and blocks ATP-induced P2rx7 signaling. We found that alcohol-damaged hepatocytes released uric acid and ATP in vivo and in vitro and that these sterile danger signals activated the inflammasome in LPS-exposed liver mononuclear cells., Conclusions: Our data indicate that the second signal in inflammasome activation and IL-1β production in ASH results from the endogenous danger signals, uric acid and ATP. Inhibition of signaling triggered by uric acid and ATP may have therapeutic implications in ASH., (Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

The Canadian Arctic is experiencing rapid changes in climatic conditions, with implications for Inuit communities widely documented. Youth have been identified as an at-risk population, with likely impacts on mental health and well-being. This study identifies and characterizes youth-specific protective factors that enhance well-being in light of a rapidly changing climate, and examines how climatic and environmental change challenges these. In-depth conversational interviews were conducted with youth aged 15-25 from the five communities of the Nunatsiavut region of Labrador, Canada: Nain, Hopedale, Postville, Makkovik, and Rigolet. Five key protective factors were identified as enhancing their mental health and well-being: being on the land; connecting to Inuit culture; strong communities; relationships with family and friends; and staying busy. Changing sea ice and weather conditions were widely reported to be compromising these protective factors by reducing access to the land, and increasing the danger of land-based activities. This study contributes to existing work on Northern climate change adaptation by identifying factors that enhance youth resilience and, if incorporated into adaptation strategies, may contribute to creating successful and effective adaptation responses., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Inflammation defines the progression of ALD from reversible to advanced stages. Translocation of bacterial LPS to the liver from the gut is necessary for alcohol-induced liver inflammation. However, it is not known whether endogenous, metabolic danger signals are required for inflammation in ALD. Uric acid and ATP, 2 major proinflammatory danger signals, were evaluated in the serum of human volunteers exposed to a single dose of ethanol or in supernatants of primary human hepatocytes exposed to ethanol. In vitro studies were used to evaluate the role of uric acid and ATP in inflammatory cross-talk between hepatocytes and immune cells. The significance of signaling downstream of uric acid and ATP in the liver was evaluated in NLRP3-deficient mice fed a Lieber-DeCarli ethanol diet. Exposure of healthy human volunteers to a single dose of ethanol resulted in increased serum levels of uric acid and ATP. In vitro, we identified hepatocytes as a significant source of these endogenous inflammatory signals. Uric acid and ATP mediated a paracrine inflammatory cross-talk between damaged hepatocytes and immune cells and significantly increased the expression of LPS-inducible cytokines, IL-1β and TNF-α, by immune cells. Deficiency of NLRP3, a ligand-sensing component of the inflammasome recognizing uric acid and ATP, prevented the development of alcohol-induced liver inflammation in mice and significantly ameliorated liver damage and steatosis. Endogenous metabolic danger signals, uric acid, and ATP are involved in inflammatory cross-talk between hepatocytes and immune cells and play a crucial role in alcohol-induced liver inflammation., (© Society for Leukocyte Biology.)

Inflammation contributes to the pathogenesis of most acute and chronic liver diseases. Inflammasomes are multiprotein complexes that can sense danger signals from damaged cells and pathogens and assemble to mediate caspase-1 activation, which proteolytically activates the cytokines IL-1β and IL-18. In contrast to other inflammatory responses, inflammasome activation uniquely requires two signals to induce inflammation, therefore setting an increased threshold. IL-1β, generated upon caspase-1 activation, provides positive feed-forward stimulation for inflammatory cytokines, thereby amplifying inflammation. Inflammasome activation has been studied in different human and experimental liver diseases and has been identified as a major contributor to hepatocyte damage, immune cell activation and amplification of liver inflammation. In this Review, we discuss the different types of inflammasomes, their activation and biological functions in the context of liver injury and disease progression. Specifically, we focus on the triggers of inflammasome activation in alcoholic steatohepatitis and NASH, chronic HCV infection, ischaemia-reperfusion injury and paracetamol-induced liver injury. The application and translation of these discoveries into therapies promises novel approaches in the treatment of inflammation in liver disease.