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Alcoholic hepatitis (AH) is a rapidly progressing and severe stage of alcoholic liver disease, presenting a grim prognosis. Extensive research has elucidated several underlying mechanisms that contribute to the development of AH, including metabolic alterations, immune stimulation, and intestinal dysbiosis. These pathological changes intricately intertwine during the progression of AH. Notably, recent studies have increasingly highlighted the pivotal role of alterations in the intestinal microbiota in the pathogenesis of AH. Consequently, future investigations should place significant emphasis on exploring the dynamics of intestinal microbiota. In this comprehensive review, we consolidate the primary causes of AH while underscoring the influence of gut microbes. Furthermore, by examining AH treatment strategies, we delineate the potential therapeutic value of interventions targeting the gut microbiota. Given the existing limitations in AH treatment options, we anticipate that this review will contribute to forthcoming research endeavors aimed at advancing AH treatment modalities. [ABSTRACT FROM AUTHOR]

Background: Alcoholic hepatitis (AH) is a severe alcoholic‐related liver disease that is a leading cause of morbidity and mortality, for which effective treatments are lacking. Brain‐expressed X‐linked gene 2 (BEX2) has been implicated in various diseases, but its association with AH has received limited attention. Thus, this study investigated BEX2's impact on the progression of AH by affecting the c‐Jun NH2‐terminal kinase/mitogen‐activated protein kinase (JNK/MAPK) pathway. Methods: Microarray dataset GSE28619 from the Gene Expression Omnibus database was used to identify differentially expressed genes in AH. Immunohistochemistry, terminal deoxynucleotidyl transferase‐mediated dUTP‐biotin nick end labeling (TUNEL), Western blot analysis, and flow cytometry were used to measure various factors in the liver tissue of AH mice. Results: BEX2 expression was significantly upregulated in the model. BEX2 gene silencing increased the levels of glutathione peroxidase and superoxide dismutase while decreasing malondialdehyde content; phosphorylation of JNK, c‐JUN, and p38MAPK; apoptosis rate; and the extent of JNK/MAPK pathway activation. Conclusions: These findings provide valuable insights into the mechanisms underlying AH development and highlight the potential role of BEX2 gene expression as a promising therapeutic target for AH. [ABSTRACT FROM AUTHOR]

Alcohol-induced gut microbiota (GM) alterations are linked to alcohol use disorder (AUD) pathogenesis. Healthy donor stool transplant (fecal microbiota transplant [FMT]) reduced alcohol desire and improved clinical outcomes in small animal and human studies. Baseline and post-therapy-related GM changes in a real-world cohort with severe alcohol-related liver disease and AUD, patterns of drinking, and relapse have not been studied. We prospectively analyzed retrospective clinical data and stored samples to examine GM alterations in a cohort of severe alcohol-associated hepatitis (SAH) patients who underwent FMT or corticosteroid treatment followed for at least 12 months. The GM changes at baseline in the context of a pattern of drinking (binge vs. every day) and baseline and post-treatment alcohol relapse status (relapser vs. non-relapser). We identified 28 patients on FMT and 25 on corticosteroids who survived 1 year post-treatment. After necessary exclusions, the final cohort for various grouped GM analysis included 16 patients in the FMT arm and 14 on corticosteroids. Pedobacter and Streptophyta species at the commencement of treatment predicted alcohol relapse in steroid-ineligible patients receiving FMT and steroid-treated patients, respectively. At 6–12 months post-FMT, non-relapsers had elevated short-chain fatty acid-producing bacterial taxa linked with lower alcohol cravings. Alcohol relapse was significantly more in those on steroid therapy and was associated with the upregulation of the nucleotide metabolism pathway related to ethanol metabolism. We demonstrate pertinent baseline and post-treatment intestinal bacterial alterations that impact patterns of AUD patterns and relapse in SAH patients in the context of the therapy offered. [ABSTRACT FROM AUTHOR]

Introduction: Although alcoholism is a common aetiological link between liver and pancreatic disorders, the frequency of coinciding pancreatic disease in patients with alcohol-related liver disease is not well understood. The present study mentions about the use of Endoscopic Ultrasound (EUS) with standardised criteria to assess asymptomatic or overt pancreatic pathology in patients with alcoholic liver disease. Aim: To determine the prevalence of asymptomatic Alcoholic Chronic Pancreatitis (ACP) in Indian patients affected by Alcoholic Liver Cirrhosis (ALC) using EUS. Materials and Methods: The present observational cross-sectional study was conducted on patients attending the Outpatient Department of Gastroenterology at Santokba Durlabhji Memorial Hospital Cum Medical Research Institute, Jaipur, Rajasthan, India. A total of 35 patients were screened with alcoholic liver disease for pancreatic abnormalities using EUS. The patients were recruited for the study over a period of 12 months, from September 2013 to August 2014. The prevalence of chronic pancreatitis (CP) was determined, and abnormalities were graded according to the Rosemont criteria. The severity of alcoholic liver disease, as indexed by Child Pugh Scoring (CPS) and Model for End-stage Liver Disease (MELD), was evaluated for any association with endosonographic findings of CP. The influence of various clinico-demographic factors on alcoholic liver and pancreatic diseases was analysed using the PSS Inc. Chicago, IL program. Results: A total of 35 male patients, aged 28 to 65 years with a mean age of 46.97 years, fulfilled the inclusion criteria. EUS revealed a prevalence of CP in 20% of patients. Three patients showed changes suggestive of CP, of which two had ALC and one had Alcoholic Hepatitis (AH). Four patients were prioritised in categorised as indeterminate for CP, with three having cirrhosis and one having Alcoholic Fatty Liver (ALF). No significant influence of clinico-demographic profiles on the final outcome parameters was observed. The patient with endoscopic changes had a MELD score of 12.85±5.11 compared to patients without changes of ACP (19.1±5.71) (p=0.013). ALC was found to be inversely related to EUS changes of ACP. Conclusion: The EUS is an effective screening tool for evaluating pancreatic abnormalities in patients with alcoholic liver disease. The present study provides a comprehensive review of previous findings in light of the varying facts and figures. As there is still a lack of experimental animal models for ALC and ACP, studies of this kind may shed light on hidden links in disease pathology. [ABSTRACT FROM AUTHOR]

Abstract Background and Aim Alcoholic hepatitis (AH), a severe complication of long‐term alcohol misuse, has a 30% 90‐day mortality. Infections are common and associated with higher mortality. There is currently no accurate method to predict infection in these patients. We aimed to test a measure of immune function, the QuantiFERON Monitor (QFM), in predicting clinical outcomes in patients with severe AH. Methods Peripheral blood was taken at baseline, and QFM performed according to the manufacturer's instructions. In parallel, QFM samples were analyzed with a cytokine multiplex. Clinical outcomes of mortality at 28 and 90 days and development of infection were recorded prospectively. Results Forty‐nine patients were recruited (mean age 51, 59% male and mean discriminant function 57.8). Interferon (IFN)‐γ release measured by standard QFM was significantly higher in survivors compared to non‐survivors at 28 (102 vs 16 IU/mL, P = 0.02) and 90 days (115 vs 32 IU/mL; P = 0.046). The area under the receiver operating characteristic curve (AUROC) was 0.79 for 28‐day mortality. IFN‐γ, IL‐10, and IL‐23 release measured by multiplex were significantly lower in patients who developed a subsequent infection compared to those who did not (115 vs 27 IU/mL, P = 0.037; 457 vs 202 pg/mL, P = 0.008; and 1039 vs 663 pg/mL, p = 0.01, respectively). Conclusion Immune dysfunction is associated with poorer outcomes in patients with severe AH. Measurement of IFN‐γ release by standard QFM accurately predicts early mortality, which can be applied to clinical practice as a biomarker of survival. Adaptation of the test to measure IL‐10 could be used as a biomarker of subsequent infection to guide clinical treatment decisions.

The review considers the principles of treatment of various forms of alcoholic liver disease from the point of view of the evidence base and clinical recommendations. The main therapy for severe alcoholic hepatitis is systemic glucocorticosteroids, their effect on survival is increased by the addition of antioxidants (N-acetylcysteine, ademethionine). The effect of ademetionine on the life expectancy of patients with alcoholic cirrhosis of ChildPugh class A and B has been proven. The treatment of patients with mild forms of alcoholic liver disease is not well developed, and the evidence base for most of the drugs used is modest.

Alcohol-related liver disease is one of the most prevalent types of chronic liver diseases globally. Alcohol-related liver disease begins with fatty liver, which further develops into hepatic inflammation, hepatocyte injury, and progresses to fibrosis and cirrhosis. Compositional changes of gut bacteria and fungi were found in patients with alcohol-related liver disease. However, the functional changes of fungi and correlations between fungi and bacteria have not been investigated. In this study, we first examined the functional capacity of fungi in patients with alcohol-related liver disease using shotgun metagenomics. Among 24 MetaCyc pathways contributed by fungi, superpathway of allantoin degradation in yeast was enriched in patients with alcoholic hepatitis. Furthermore, we compared the predictive power of bacteria versus fungi and found that bacteria performed better than fungi to separate patients with alcoholic hepatitis from non-alcoholic controls and patients with alcohol use disorder. Finally, we investigated the associations between the intestinal fungi and bacteria in alcoholic hepatitis patients. Positive association between fungi and bacteria was found between Cladosporium and Gemmiger, meanwhile negative association was found between Cryptococcus and Pseudomonas in alcoholic hepatitis patients.

Effective therapies for alcohol-associated liver disease (ALD) are limited; therefore, the discovery of new therapeutic agents is greatly warranted. Toll-like receptor 7 (TLR7) is a pattern recognition receptor for single-stranded RNA, and its activation prevents liver fibrosis. We examined liver and intestinal damage in Tlr7-/- mice to determine the role of TLR7 in ALD pathogenesis. In an alcoholic hepatitis (AH) mouse model, hepatic steatosis, injury, and inflammation were induced by chronic binge ethanol feeding in mice, and Tlr7 deficiency exacerbated these effects. Because these results demonstrated that endogenous TLR7 signaling activation is protective in the AH mouse model, we hypothesized that TLR7 activation may be an effective therapeutic strategy for ALD. Therefore, we investigated the therapeutic effect of TLR7 agonistic agent, 1Z1, in the AH mouse model. Oral administration of 1Z1 was well tolerated and prevented intestinal barrier disruption and bacterial translocation, which thus suppressed ethanol-induced hepatic injury, steatosis, and inflammation. Furthermore, 1Z1 treatment up-regulated the expression of antimicrobial peptides, Reg3b and Reg3g, in the intestinal epithelium, which modulated the microbiome by decreasing and increasing the amount of Bacteroides and Lactobacillus, respectively. Additionally, 1Z1 up-regulated intestinal interleukin (IL)-22 expression. IL-22 deficiency abolished the protective effects of 1Z1 in ethanol-induced liver and intestinal damage, suggesting intestinal IL-22 as a crucial mediator for 1Z1-mediated protection in the AH mouse model. Collectively, our results indicate that TLR7 signaling exerts protective effects in the AH mouse model and that a TLR7 ligand, 1Z1, holds therapeutic potential for the treatment of AH.

This study was performed to investigate the protective effects of Allium ochotense on fatty liver and hepatitis in chronic alcohol-induced hepatotoxicity. The physiological compounds of a mixture of aqueous and 60% ethanol (2:8, w/w) extracts of A. ochotense (EA) were identified as kestose, raffinose, kaempferol and quercetin glucoside, and kaempferol di-glucoside by UPLC Q-TOF MSE. The EA regulated the levels of lipid metabolism-related biomarkers such as total cholesterol, triglyceride, low-density lipoprotein (LDL), and high-density lipoprotein (HDL)-cholesterol in serum. Also, EA ameliorated the levels of liver toxicity-related biomarkers such as glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), and total bilirubin in serum. EA improved the antioxidant system by reducing malondialdehyde contents and increasing superoxide dismutase (SOD) levels and reduced glutathione content. EA improved the alcohol metabolizing enzymes such as alcohol dehydrogenase, acetaldehyde dehydrogenase, and cytochrome P450 2E1 (CYP2E1). Treatment with EA alleviated lipid accumulation-related protein expression by improving phosphorylation of AMP-activated protein kinase (p-AMPK) expression levels. Especially, EA reduced inflammatory response by regulating the toll-like receptor–4/nuclear factor kappa-light-chain-enhancer of activated B cells (TLR-4/NF-κB) signaling pathway. EA showed an anti-apoptotic effect by regulating the expression levels of B-cell lymphoma 2 (BCl-2), BCl-2-associated X protein (BAX), and caspase 3. Treatment with EA also ameliorated liver fibrosis via inhibition of transforming growth factor-beta 1/suppressor of mothers against decapentaplegic (TGF-β1/Smad) pathway and alpha-smooth muscle actin (α-SMA). Therefore, these results suggest that EA might be a potential prophylactic agent for the treatment of alcoholic liver disease.

The socioeconomic burden of alcohol‐related liver disease has been increasing worldwide. Its prevalence is underestimated, and patients with alcohol‐related liver disease are rarely diagnosed in the earlier phase of the disease spectrum. Alcoholic hepatitis is a distinct syndrome with life‐threatening signs of systemic inflammation. In severe alcoholic hepatitis, prednisolone is indicated as the first‐line treatment even with the possibility of various complications. Early liver transplantation can be another option for highly selected patients with a null response to prednisolone. Most importantly, abstinence is the mainstay of long‐term care, but relapse is frequent among patients. Recent findings on the pathogenesis of alcoholic hepatitis have enabled us to discover new therapeutic targets. Preventing hepatic inflammation, reducing oxidative stress, improving gut dysbiosis, and enhancing liver regeneration are the main targets of emerging therapies. Herein, we review the pathogenesis, current treatment, and barriers to successful clinical trials of alcoholic hepatitis. Additionally, clinical trials for alcoholic hepatitis, either ongoing or recently completed, will be briefly introduced. [ABSTRACT FROM AUTHOR]

Liver transplantation offers live-saving therapy for patients with complications of cirrhosis and stage T2 hepatocellular carcinoma. The demand for organs far outstrips the supply, and innovations aimed at increasing the number of usable deceased donors as well as alternative donor sources are a major focus. The etiologies of cirrhosis are shifting over time, with more need for transplantation among patients with alcohol-associated liver disease and nonalcoholic/metabolic fatty liver disease and less for viral hepatitis, although hepatitis B remains an important indication for transplant in countries with high endemicity. The rise in transplantation for alcohol-associated liver disease and nonalcoholic/metabolic fatty liver disease has brought attention to how patients are selected for transplantation and the strategies needed to prevent recurrent disease. In this review, we present a status report on the most pressing topics in liver transplantation and future challenges. [ABSTRACT FROM AUTHOR]

The following review article presents clinical and experimental features of alcohol-induced liver disease (ALD). Basic aspects of alcohol metabolism leading to the development of liver hepatotoxicity are discussed. ALD includes fatty liver, acute alcoholic hepatitis with or without liver failure, alcoholic steatohepatitis (ASH) leading to fibrosis and cirrhosis, and hepatocellular cancer (HCC). ALD is fully attributable to alcohol consumption. However, only 10-20% of heavy drinkers (persons consuming more than 40 g of ethanol/day) develop clinical ALD. Moreover, there is a link between behaviour and environmental factors that determine the amount of alcohol misuse and their liver disease. The range of clinical presentation varies from reversible alcoholic hepatic steatosis to cirrhosis, hepatic failure, and hepatocellular carcinoma. We aimed to (1) describe the clinico-pathology of ALD, (2) examine the role of immune responses in the development of alcoholic hepatitis (ASH), (3) propose diagnostic markers of ASH, (4) analyze the experimental models of ALD, (5) study the role of alcohol in changing the microbiota, and (6) articulate how findings in the liver and/or intestine influence the brain (and/or vice versa) on ASH; (7) identify pathways in alcohol-induced organ damage and (8) to target new innovative experimental concepts modeling the experimental approaches. The present review includes evidence recognizing the key toxic role of alcohol in ALD severity. Cytochrome p450 CYP2E1 activation may change the severity of ASH. The microbiota is a key element in immune responses, being an inducer of proinflammatory T helper 17 cells and regulatory T cells in the intestine. Alcohol consumption changes the intestinal microbiota and influences liver steatosis and liver inflammation. Knowing how to exploit the microbiome to modulate the immune system might lead to a new form of personalized medicine in ALF and ASH.

Alcoholism is one of the leading and increasingly prevalent reasons of liver associated morbidity and mortality worldwide. Alcoholic hepatitis (AH) constitutes a severe disease with currently no satisfying treatment options. Lipoxin A4 (LXA4), a 15-lipoxygenase (ALOX15)-dependent lipid mediator involved in resolution of inflammation, showed promising pre-clinical results in the therapy of several inflammatory diseases. Since inflammation is a main driver of disease progression in alcoholic hepatitis, we investigated the impact of endogenous ALOX15-dependent lipid mediators and exogenously applied LXA4 on AH development. A mouse model for alcoholic steatohepatitis (NIAAA model) was tested in Alox12/15+/+ and Alox12/15-/- mice, with or without supplementation of LXA4. Absence of Alox12/15 aggravated parameters of liver disease, increased hepatic immune cell infiltration in AH, and elevated systemic neutrophils as a marker for systemic inflammation. Interestingly, i.p. injections of LXA4 significantly lowered transaminase levels only in Alox12/15-/- mice and reduced hepatic immune cell infiltration as well as systemic inflammatory cytokine expression in both genotypes, even though steatosis progressed. Thus, while LXA4 injection attenuated selected parameters of disease progression in Alox12/15-/- mice, its beneficial impact on immunity was also apparent in Alox12/15+/+ mice. In conclusion, pro-resolving lipid mediators may be beneficial to reduce inflammation in alcoholic hepatitis.

Background. An analysis of published results on the chemical structure, pharmacodynamics and pharmacokinetics of hepatoprotective agents, as well as their practical application, shows that a holistic view on the pharmacology of hepatoprotective agents is yet to be developed. Thus, the relationship between antioxidant activity and the effectiveness of reducing hepatocyte cytolysis remains unclear. Another difficult question concerns indications for the application of hepatoprotectors, selection of a particular drug and treatment duration.Objectives. To investigate the effects of hepatoprotective agents with different mechanisms of action on the indicators of oxidative metabolism in the blood of patients with alcoholic hepatitis.Methods. Four groups of patients were involved in the study. The 1st group consisted of relatively healthy male patients (n = 15). The remaining groups (10 individuals in each) were represented by patients with moderate alcoholic hepatitis. Patients of the 2nd group received remaxol; patients of the 3rd group received ademetionine; patients of the 4th group received ursodeoxycholic acid. Prior to and following treatment, the indicators of cytolysis and oxidative stress in blood were determined. Statistical data processing was carried out using the StatPlus v 7 (AnalystSoft Inc.) software package.Results. According to the observed changes in the cytolytic syndrome marker enzymes, all three hepatoprotectors under study expressed comparable efficacy. After treatment according to any of the applied schemes, the ALT and AST activity in the blood plasma decreased by 56–68% and 75–81%, respectively, compared to their initial values. In comparison with the control group, the total antioxidant activity of the blood plasma decreased by 20–27%; the content of TBA-reactive products in the erythrocyte suspension increased by 61–87%. The remaxol, ademethionine or ursodeoxycholic acid therapy led to a partial normalization of the abovementioned parameters without significant differences between the experimental groups. The concentration of reduced glutathione in the erythrocyte suspension and the content of thiol groups in the blood plasma of patients were reduced in comparison with the control group by 16% and 26%, respectively. After therapy, these indicators also increased by 12–15%, although no predominant effect of either of the studied hepatoprotectors was revealed.Conclusion. The conducted comparative study indicated the absence of a specific antioxidant effect among the pharmacological mechanisms of action of remaxol, ademethionine and ursodeoxycholic acid. In this regard, further research should be carried out to investigate the effect of hepatoprotective drugs on pathobiochemical changes and to analyse a relationship between the antioxidant effect and the efficacy of reducing the level of hepatocyte cytolysis.

Background & Aims: Src homology and collagen (Shc) proteins are major adapters to extracellular signals, however, the regulatory role of Shc isoforms in sterile inflammatory responses in alcoholic hepatitis (AH) has not been fully investigated. We hypothesized that in an isoform-specific manner Shc modulates pre-apoptotic signals, calreticulin (CRT) membrane exposure, and recruitment of inflammatory cells. Methods: Liver biopsy samples from patients with AH vs healthy subjects were studied for Shc expression using DNA microarray data and immunohistochemistry. Shc knockdown (hypomorph) and age-matched wild-type mice were pair-fed according to the chronic-plus-binge alcohol diet. To analyze hepatocyte-specific effects, adeno-associated virus 8–thyroxine binding globulin–Cre (hepatocyte-specific Shc knockout)-mediated deletion was performed in flox/flox Shc mice. Lipid peroxidation, proinflammatory signals, redox radicals, reduced nicotinamide adenine dinucleotide/oxidized nicotinamide adenine dinucleotide ratio, as well as cleaved caspase 8, B-cell–receptor–associated protein 31 (BAP31), Bcl-2–associated X protein (Bax), and Bcl-2 homologous antagonist killer (Bak), were assessed in vivo. CRT translocation was studied in ethanol-exposed p46ShcẟSH2-transfected hepatocytes by membrane biotinylation in conjunction with phosphorylated-eukaryotic initiation factor 2 alpha, BAP31, caspase 8, and Bax/Bak. The effects of idebenone, a novel Shc inhibitor, was studied in alcohol/pair-fed mice. Results: Shc was significantly induced in patients with AH (P < .01). Alanine aminotransferase, reduced nicotinamide adenine dinucleotide/oxidized nicotinamide adenine dinucleotide ratios, production of redox radicals, and lipid peroxidation improved (P < .05), and interleukin 1β, monocyte chemoattractant protein 1, and C-X-C chemokine ligand 10 were reduced in Shc knockdown and hepatocyte-specific Shc knockout mice. In vivo, Shc-dependent induction, and, in hepatocytes, a p46Shc-dependent increase in pre-apoptotic proteins Bax/Bak, caspase 8, BAP31 cleavage, and membrane translocation of CRT/endoplasmic reticulum-resident protein 57 were seen. Idebenone protected against alcohol-mediated liver injury. Conclusions: Alcohol induces p46Shc-dependent activation of pre-apoptotic pathways and translocation of CRT to the membrane, where it acts as a damage-associated molecular pattern, instigating immunogenicity. Shc inhibition could be a novel treatment strategy in AH.

Background and Aims: Thrombocytopenia is present in up to 76% of patients with chronic liver disease, and lower platelet counts (PCs) are associated with greater severity of portal hypertension. In this study, we assess the relationship of PC in patients with a clinical diagnosis of severe alcoholic hepatitis (SAH) with clinical severity and response to corticosteroid (CS) therapy. Methods: Clinical characteristics, treatment, and hospital outcomes for patients admitted with SAH were analyzed from an electronic health record system. Patients were categorized based on admission PC (k/uL) into 5 categories:

Alcoholic hepatitis is a major health and economic burden worldwide. Glucocorticoids (GCs) are the only first-line drugs recommended to treat severe alcoholic hepatitis (sAH), with limited short-term efficacy and significant side effects. In this review, I summarize the major benefits and side effects of GC therapy in sAH and the potential underlying mechanisms. The review of the literature and data mining clearly indicate that the hepatic signaling of glucocorticoid receptor (GR) is markedly impaired in sAH patients. The impaired GR signaling causes hepatic down-regulation of genes essential for gluconeogenesis, lipid catabolism, cytoprotection, and anti-inflammation in sAH patients. The efficacy of GCs in sAH may be compromised by GC resistance and/or GC’s extrahepatic side effects, particularly the side effects of intestinal epithelial GR on gut permeability and inflammation in AH. Prednisolone, a major GC used for sAH, activates both the GR and mineralocorticoid receptor (MR). When GC non-responsiveness occurs in sAH patients, the activation of MR by prednisolone might increase the risk of alcohol abuse, liver fibrosis, and acute kidney injury. To improve the GC therapy of sAH, the effort should be focused on developing the biomarker(s) for GC responsiveness, liver-targeting GR agonists, and strategies to overcome GC non-responsiveness and prevent alcohol relapse in sAH patients.

This audit collates data on alcohol‐related gastrointestinal (GI) admissions at Monash Health, Victoria, during the prolonged, coronavirus disease 2019 (COVID‐19)–related lockdown July to October 2020 compared with the same periods in 2019 and 2021. We found a 58% increase in admissions in 2020 and a 16% increase in 2021, which also increased disproportionately to overall health service emergency presentations. Self‐reported alcohol consumption increased by 2.5‐fold and was greatest in 2020. Clinical severity was unchanged and cirrhosis was the only factor associated with severe disease. This study suggests an association between the pandemic‐related lockdown, alcohol consumption and alcohol‐related GI hospitalisation. Our study provides support for resourcing and adapting alcohol and other drug services during and beyond the COVID‐19 lockdown. [ABSTRACT FROM AUTHOR]

Alcohol-associated hepatitis has a poor prognosis in terms of short-term mortality and often presents with symptoms, such as jaundice, acute renal failure, and ascites. There are many prognostic models that have been developed to predict short-term and long-term mortality in these patients. Current prognostic models can be divided into static scores, which are measured at admission, and dynamic models, which measure baseline and after a certain amount of time. The efficacy of these models in predicting short-term mortality is disputed. Numerous studies across the world have compared prognostic models, such as the Maddrey's discriminant function, the model for end-stage liver disease score, model for end-stage liver disease score-Na, Glasgow alcohol-associated hepatitis score, and the age-bilirubin-international normalized ratio-creatinine (ABIC) score, to each other to determine which score is more useful for a particular context. There are also prognostic markers such as liver biopsy, breath biomarkers, and acute kidney injury that are able to predict mortality. The accuracy of these scores is a key to determining when treatment with corticosteroids is futile since there is an increased risk of infection in those treated with it. Furthermore, although these scores are helpful in predicting short-term mortality, the only factor that is able to predict long-term mortality in patients with alcohol-related liver disease is abstinence. Numerous studies have proven that even though corticosteroids provide a treatment for alcohol-associated hepatitis, it is a temporary one, at best. The purpose of this paper is to compare the historical models to current ones in their ability to predict mortality in patients with alcohol-related liver disease by analyzing multiple studies that have examined these prognostic markers. This paper also isolates the knowledge gaps in the ability to delineate which patients would benefit from corticosteroids and patients who would not and provides potential models for the future that could narrow this gap. [ABSTRACT FROM AUTHOR]

Introduction and Objectives: Psychosocial stressors related to the coronavirus-19 (COVID-19) pandemic increased alcohol consumption. The effect on patients with alcohol-related liver diseases remains unclear. Materials and Methods: Hospitalizations at a tertiary care center due to alcohol-related liver disease from March 1 through August 31 in 2019 (pre-pandemic cohort) and 2020 (pandemic cohort) were reviewed retrospectively. Differences in patient demographics, disease features, and outcomes were estimated in patients with alcoholic hepatitis utilizing T-tests, Mann-Whitney tests, Chi-square and Fisher Exact Tests and Anova models and logistic regression models in patients with alcoholic cirrhosis. Results: 146 patients with alcoholic hepatitis and 305 patients with alcoholic cirrhosis were admitted during the pandemic compared to 75 and 396 in the pre-pandemic cohort. Despite similar median Maddrey Scores (41.20 vs. 37.45, p=0.57), patients were 25% less likely to receive steroids during the pandemic. Patients with alcoholic hepatitis admitted during the pandemic were more likely to have hepatic encephalopathy (0.13; 95% CI:0.01, 0.25), variceal hemorrhage (0.14; 95% CI:0.04, 0.25), require oxygen (0.11; 95% CI:0.01, 0.21), vasopressors (OR:3.49; 95% CI:1.27, 12.01) and hemodialysis (OR:3.70; 95% CI:1.22, 15.13). On average, patients with alcoholic cirrhosis had MELD-Na scores 3.77 points higher (95% CI:1.05, 13.46) as compared to the pre-pandemic and had higher odds of experiencing hepatic encephalopathy (OR:1.34; 95% CI:1.04, 1.73), spontaneous bacterial peritonitis (OR:1.88; 95% CI:1.03, 3.43), ascites (OR:1.40, 95% CI:1.10, 1.79), vasopressors (OR:1.68, 95% CI:1.14, 2.46) or inpatient mortality (OR:2.00, 95% CI:1.33, 2.99) than the pre-pandemic. Conclusions: Patients with alcohol-related liver disease experienced worse outcomes during the pandemic. [ABSTRACT FROM AUTHOR]

The rate of alcoholic hepatitis (AH) has risen in recent years. AH can cause as much as 40–50% mortality in severe cases. Successful abstinence has been the only therapy associated with long-term survival in patients with AH. Thus, it is crucial to be able to identify at-risk individuals in order to implement preventative measures. From the patient database, adult patients (age 18 and above) with AH were identified using the ICD-10 classification from November 2017 to October 2019. Liver biopsies are not routinely performed at our institution. Therefore, patients were diagnosed with AH based on clinical parameters and were divided into "probable" and "possible" AH. Logistic regression analysis was performed to determine risk factors associated with AH. A sub-analysis was performed to determine variables associated with mortality in AH patients. Among the 192 patients with alcohol dependence, there were 100 patients with AH and 92 patients without AH. The mean age was 49.3 years in the AH cohort, compared to 54.5 years in the non-AH cohort. Binge drinking (OR 2.698; 95% CI 1.079, 6.745; p = 0.03), heavy drinking (OR 3.169; 95% CI 1.348, 7.452; p = 0.01), and the presence of cirrhosis (OR 3.392; 95% CI 1.306, 8.811; p = 0.01) were identified as characteristics more commonly found in the AH cohort. Further, a higher inpatient mortality was seen in those with a probable AH diagnosis (OR 6.79; 95% CI 1.38, 44.9; p = 0.03) and hypertension (OR 6.51; 95% CI 9.49, 35.7; p = 0.02). A higher incidence of mortality was also noted among the non-Caucasian race (OR 2.72; 95% CI 4.92; 22.3; p = 0.29). A higher mortality rate despite a lower incidence of alcohol use among non-Caucasian patients may indicate healthcare disparities. [ABSTRACT FROM AUTHOR]

Background and Aim: Alcoholic hepatitis (AH), a severe complication of long‐term alcohol misuse, has a 30% 90‐day mortality. Infections are common and associated with higher mortality. There is currently no accurate method to predict infection in these patients. We aimed to test a measure of immune function, the QuantiFERON Monitor (QFM), in predicting clinical outcomes in patients with severe AH. Methods: Peripheral blood was taken at baseline, and QFM performed according to the manufacturer's instructions. In parallel, QFM samples were analyzed with a cytokine multiplex. Clinical outcomes of mortality at 28 and 90 days and development of infection were recorded prospectively. Results: Forty‐nine patients were recruited (mean age 51, 59% male and mean discriminant function 57.8). Interferon (IFN)‐γ release measured by standard QFM was significantly higher in survivors compared to non‐survivors at 28 (102 vs 16 IU/mL, P = 0.02) and 90 days (115 vs 32 IU/mL; P = 0.046). The area under the receiver operating characteristic curve (AUROC) was 0.79 for 28‐day mortality. IFN‐γ, IL‐10, and IL‐23 release measured by multiplex were significantly lower in patients who developed a subsequent infection compared to those who did not (115 vs 27 IU/mL, P = 0.037; 457 vs 202 pg/mL, P = 0.008; and 1039 vs 663 pg/mL, p = 0.01, respectively). Conclusion: Immune dysfunction is associated with poorer outcomes in patients with severe AH. Measurement of IFN‐γ release by standard QFM accurately predicts early mortality, which can be applied to clinical practice as a biomarker of survival. Adaptation of the test to measure IL‐10 could be used as a biomarker of subsequent infection to guide clinical treatment decisions. [ABSTRACT FROM AUTHOR]

Background and Aim: Roux-En-Y gastric bypass (RYGB) is associated with risk of alcohol use disorder. The impact of RYGB among patients with alcohol-associated liver disease (ALD) remains unknown. Methods: A retrospective cohort from National Inpatient Sample (01/2006–09/2015) database on 421,156 admissions with alcohol-associated cirrhosis (AC) was stratified for non-primary discharge diagnosis of previous RYGB. Admissions with RYGB (cases) were matched 1:3 to without RYGB (controls) based on propensity score on demographics, calendar year, socioeconomic status (insurance and zip code income quartile), obesity, diabetes, anxiety, and alcohol use disorder. Primary outcome was concomitant discharge diagnosis of alcoholic hepatitis (AH) or development of acute on chronic liver failure (ACLF). Results: Of 10,168 admissions (mean age 49 yrs., 75% females, 79% whites), cases (N = 2542) vs. controls had higher prevalence of concomitant AH (18.8 vs. 17%, P = 0.032), hepatic encephalopathy (31 vs. 25%), infection (28 vs. 24%), and grade 3 ACLF (13 vs. 5%), P < 0.001. Conditional logistic regression models showed higher odds for AH, hepatic encephalopathy, and infection among cases. In-hospital mortality of 6.3% (43% in ACLF) was lower in cases, but similar in the sub-cohorts of AH (N = 1768) or ACLF (N = 768). Results were similar in a sensitivity analysis of matched cohort of 2016 hospitalizations (504 cases) with primary discharge diagnosis of AC. Conclusion: Among patients with AC, previous RYGB is associated with increased likelihood of concomitant AH, hepatic encephalopathy, and infection, but similar in-hospital mortality. Prospective studies are needed to validate, determine causality, and understand mechanisms of these findings among patients with alcohol-associated cirrhosis. [ABSTRACT FROM AUTHOR]

Background & Aims: Model for End-Stage Liver Disease (MELD) score better predicts mortality in alcohol-associated hepatitis (AH) but could underestimate severity in women and malnourished patients. Using a global cohort, we assessed the ability of the MELD 3.0 score to predict short-term mortality in AH. Methods: This was a retrospective cohort study of patients admitted to hospital with AH from 2009 to 2019. The main outcome was all-cause 30-day mortality. We compared the AUC using DeLong's method and also performed a time-dependent AUC with competing risks analysis. Results: A total of 2,124 patients were included from 28 centres from 10 countries on three continents (median age 47.2 ± 11.2 years, 29.9% women, 71.3% with underlying cirrhosis). The median MELD 3.0 score at admission was 25 (20–33), with an estimated survival of 73.7% at 30 days. The MELD 3.0 score had a better performance in predicting 30-day mortality (AUC:0.761, 95%CI:0.732–0.791) compared with MELD sodium (MELD-Na; AUC: 0.744, 95% CI: 0.713–0.775; p = 0.042) and Maddrey’s discriminant function (mDF) (AUC: 0.724, 95% CI: 0.691–0.757; p = 0.013). However, MELD 3.0 did not perform better than traditional MELD (AUC: 0.753, 95% CI: 0.723–0.783; p = 0.300) and Age-Bilirubin-International Normalised Ratio-Creatinine (ABIC) (AUC:0.757, 95% CI: 0.727–0.788; p = 0.765). These results were consistent in competing-risk analysis, where MELD 3.0 (AUC: 0.757, 95% CI: 0.724–0.790) predicted better 30-day mortality compared with MELD-Na (AUC: 0.739, 95% CI: 0.708–0.770; p = 0.028) and mDF (AUC:0.717, 95% CI: 0.687–0.748; p = 0.042). The MELD 3.0 score was significantly better in predicting renal replacement therapy requirements during admission compared with the other scores (AUC: 0.844, 95% CI: 0.805–0.883). Conclusions: MELD 3.0 demonstrated better performance compared with MELD-Na and mDF in predicting 30-day and 90-day mortality, and was the best predictor of renal replacement therapy requirements during admission for AH. However, further prospective studies are needed to validate its extensive use in AH. Impact and implications: Severe AH has high short-term mortality. The establishment of treatments and liver transplantation depends on mortality prediction. We evaluated the performance of the new MELD 3.0 score to predict short-term mortality in AH in a large global cohort. MELD 3.0 performed better in predicting 30- and 90-day mortality compared with MELD-Na and mDF, but was similar to MELD and ABIC scores. MELD 3.0 was the best predictor of renal replacement therapy requirements. Thus, further prospective studies are needed to support the wide use of MELD 3.0 in AH.

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has been suggested to purpose threats to health of mankind. Alcoholic hepatitis (AH) is a life‐threatening acute and chronic liver failure that takes place in sufferers who drink excessively. During the epidemic, AH has an increasing incidence of severe illness and mortality. The intrinsic relationship of molecular pathogenesis, as well as common therapeutic strategies for two diseases are still poorly understood. The transcriptome of the COVID‐19 and AH has been compared to obtain the altered genes and hub genes were screened out through protein–protein interaction (PPI) network analysis. Via gene ontology (GO), pathway enrichment, and transcription regulator analysis, a deeper appreciation of the interplay mechanism between hub genes were established. Finally, gene‐disease and gene–drug analysis were displayed to instruct the clinical treatments. With 181 common differentially expressed genes (DEGs) of AH and COVID‐19 were obtained, 10 hub genes were captured. Follow‐up studies located that these 10 genes typically mediated the diseases occurrence by regulating the activities of the immune system. Other results suggest that the common pathways of the two ailments are enriched in regulating the function of immune cells and release of immune molecules. The top 10 drug candidates have been chosen primarily, some of which have been proved effective in treating AH sufferers infected with COVID‐19. This study reveals the common pathogenesis of COVID‐19 and AH and assist to discover necessary therapeutic targets to combat the ongoing pandemic induced via SARS‐CoV‐2 infection and acquire promising remedy strategies for the two diseases.

Alcohol-related liver disease (ALD) encompasses a range of pathological conditions that are complex to study at the clinical and preclinical levels. Despite the global burden of ALD, there is a lack of effective treatments, and mortality is high. One of the reasons for the unsuccessful development of novel therapies is that experimental studies are hindered by the challenge of recapitulating this multifactorial disorder in vitro, including the contributions of hepatotoxicity, impaired lipid metabolism, fibrosis and inflammatory cytokine storm, which are critical drivers in the pathogenesis of ALD in patients and primary targets for drug development. Here, we present the unique characteristics of the culture of human precision-cut liver slices (PCLS) to replicate key disease processes in ALD. PCLS were prepared from human liver specimens and treated with ethanol alone or in combination with fatty acids and lipopolysaccharide (FA + LPS) for up to 5 days to induce hepatotoxic, inflammatory and fibrotic events associated with ALD. Alcohol insult induced hepatocyte death which was more pronounced with the addition of FA + LPS. This mixture showed a significant increase in the cytokines conventionally associated with the prototypical inflammatory response observed in severe ALD, and interestingly, alcohol alone exhibited a different effect. Profibrogenic activation was also observed in the slices and investigated in the context of slice preparation. These results support the versatility of this organotypic model to study different pathways involved in alcohol-induced liver damage and ALD progression and highlight the applicability of the PCLS for drug discovery, confirming their relevance as a bridge between preclinical and clinical studies.

Splenic infarction without splenic vessel thrombosis is an infrequent presentation in clinical practice. The case discussed here is a 45-year-old male with a history of alcohol abuse, who presented to the hospital with pain abdomen epicentered in the left upper quadrant. On evaluation, the patient was found to be having portal hypertension complicated with alcoholic hepatitis, acute necrotizing pancreatitis, gastric, and paraesophageal varices. The presence of splenic infarction without concomitant splenic vessel thrombosis in this patient merits a discussion of relevant investigations and their findings thereof.

Heavy alcohol use is the cause of alcoholic liver disease (ALD). The ALD spectrum ranges from alcoholic steatosis to steatohepatitis, fibrosis, and cirrhosis. In Western countries, approximately 50% of cirrhosis-related deaths are due to alcohol use. While alcoholic cirrhosis is no longer considered a completely irreversible condition, no effective anti-fibrotic therapies are currently available. Another significant clinical aspect of ALD is alcoholic hepatitis (AH). AH is an acute inflammatory condition that is often comorbid with cirrhosis, and severe AH has a high mortality rate. Therapeutic options for ALD are limited. The established treatment for AH is corticosteroids, which improve short-term survival but do not affect long-term survival. Liver transplantation is a curative treatment option for alcoholic cirrhosis and AH, but patients must abstain from alcohol use for 6 months to qualify. Additional effective therapies are needed. The molecular mechanisms underlying ALD are complex and have not been fully elucidated. Various molecules, signaling pathways, and crosstalk between multiple hepatic and extrahepatic cells contribute to ALD progression. This review highlights established and emerging concepts in ALD clinicopathology, their underlying molecular mechanisms, and current and future ALD treatment options.

Introduction and Objectives: Psychosocial stressors related to the coronavirus-19 (COVID-19) pandemic increased alcohol consumption. The effect on patients with alcohol-related liver diseases remains unclear. Materials and Methods: Hospitalizations at a tertiary care center due to alcohol-related liver disease from March 1 through August 31 in 2019 (pre-pandemic cohort) and 2020 (pandemic cohort) were reviewed retrospectively. Differences in patient demographics, disease features, and outcomes were estimated in patients with alcoholic hepatitis utilizing T-tests, Mann-Whitney tests, Chi-square and Fisher Exact Tests and Anova models and logistic regression models in patients with alcoholic cirrhosis. Results: 146 patients with alcoholic hepatitis and 305 patients with alcoholic cirrhosis were admitted during the pandemic compared to 75 and 396 in the pre-pandemic cohort. Despite similar median Maddrey Scores (41.20 vs. 37.45, p=0.57), patients were 25% less likely to receive steroids during the pandemic. Patients with alcoholic hepatitis admitted during the pandemic were more likely to have hepatic encephalopathy (0.13; 95% CI:0.01, 0.25), variceal hemorrhage (0.14; 95% CI:0.04, 0.25), require oxygen (0.11; 95% CI:0.01, 0.21), vasopressors (OR:3.49; 95% CI:1.27, 12.01) and hemodialysis (OR:3.70; 95% CI:1.22, 15.13). On average, patients with alcoholic cirrhosis had MELD-Na scores 3.77 points higher (95% CI:1.05, 13.46) as compared to the pre-pandemic and had higher odds of experiencing hepatic encephalopathy (OR:1.34; 95% CI:1.04, 1.73), spontaneous bacterial peritonitis (OR:1.88; 95% CI:1.03, 3.43), ascites (OR:1.40, 95% CI:1.10, 1.79), vasopressors (OR:1.68, 95% CI:1.14, 2.46) or inpatient mortality (OR:2.00, 95% CI:1.33, 2.99) than the pre-pandemic. Conclusions: Patients with alcohol-related liver disease experienced worse outcomes during the pandemic.

BackgroundsAlcoholic hepatitis (AH) is a major health problem worldwide. There is increasing evidence that immune cells, iron metabolism and copper metabolism play important roles in the development of AH. We aimed to explore biomarkers that are co-associated with M1 macrophages, ferroptosis and cuproptosis in AH patients.MethodsGSE28619 and GSE103580 datasets were integrated, CIBERSORT algorithm was used to analyze the infiltration of 22 types of immune cells and GSVA algorithm was used to calculate ferroptosis and cuproptosis scores. Using the “WGCNA” R package, we established a gene co-expression network and analyzed the correlation between M1 macrophages, ferroptosis and cuproptosis scores and module characteristic genes. Subsequently, candidate genes were screened by WGCNA and differential expression gene analysis. The LASSO-SVM analysis was used to identify biomarkers co-associated with M1 macrophages, ferroptosis and cuproptosis. Finally, we validated these potential biomarkers using GEO datasets (GSE155907, GSE142530 and GSE97234) and a mouse model of AH.ResultsThe infiltration level of M1 macrophages was significantly increased in AH patients. Ferroptosis and cuproptosis scores were also increased in AH patients. In addition, M1 macrophages, ferroptosis and cuproptosis were positively correlated with each other. Combining bioinformatics analysis with a mouse model of AH, we found that ALDOA, COL3A1, LUM, THBS2 and TIMP1 may be potential biomarkers co-associated with M1 macrophages, ferroptosis and cuproptosis in AH patients.ConclusionWe identified 5 potential biomarkers that are promising new targets for the treatment and diagnosis of AH patients.

Alcoholic liver disease (ALD) is a consequence of excessive alcohol use. According to many studies, alcohol represents a significant socioeconomic and health risk factor in today's population. According to data from the World Health Organization, there are about 75 million people who have alcohol disorders, and it is well known that its use leads to serious health problems. ALD is a multimodality spectrum that includes alcoholic fatty liver disease (AFL) and alcoholic steatohepatitis (ASH), consequently leading to liver fibrosis and cirrhosis. In addition, the rapid progression of alcoholic liver disease can lead to alcoholic hepatitis (AH). Alcohol metabolism produces toxic metabolites that lead to tissue and organ damage through an inflammatory cascade that includes numerous cytokines, chemokines, and reactive oxygen species (ROS). In the process of inflammation, mediators are cells of the immune system, but also resident cells of the liver, such as hepatocytes, hepatic stellate cells, and Kupffer cells. These cells are activated by exogenous and endogenous antigens, which are called pathogen and damage-associated molecular patterns (PAMPs, DAMPs). Both are recognized by Toll-like receptors (TLRs), which activation triggers the inflammatory pathways. It has been proven that intestinal dysbiosis and disturbed integrity of the intestinal barrier perform a role in the promotion of inflammatory liver damage. These phenomena are also found in chronic excessive use of alcohol. The intestinal microbiota has an important role in maintaining the homeostasis of the organism, and its role in the treatment of ALD has been widely investigated. Prebiotics, probiotics, postbiotics, and symbiotics represent therapeutic interventions that can have a significant effect on the prevention and treatment of ALD. [ABSTRACT FROM AUTHOR]

Cases of alcohol-associated liver disease (ALD) are increasing at a steady rate in the United States with more patients presenting with alcohol-associated hepatitis and alcohol-associated cirrhosis. While alcohol use has increased across many demographic groups, women are suffering from a greater increase in alcohol use disorder (AUD), and are at a greater risk of ALD due to pathophysiological differences which include absorption of alcohol, first pass metabolism, and hormonal differences. Differences across race have also been found with Native Americans and Hispanics suffering from some of the largest increases in ALD rates. Younger adults are heavily impacted by rising rates of both AUD and ALD. Comorbidities such as obesity and NASH have been shown to augment the deleterious effects of AUD and ALD, resulting in more advanced liver disease. Finally, COVID-19 and policies related to the pandemic have resulted in increased AUD across many cohorts, which have resulted in marked increases in ALD. In conclusion, ALD rates are rising, with young people and women particularly impacted. [ABSTRACT FROM AUTHOR]

Alcohol-associated liver disease is a leading cause of mortality and morbidity worldwide. Patients with alcohol-associated liver disease are often diagnosed at advanced stage and disease spectrum including alcoholic hepatitis, a severe manifestation with a high short-term mortality. Corticosteroid, recommended first-line treatment for patients with alcoholic hepatitis, is a very suboptimal treatment. Although the use of early liver transplantation has increased with consistent benefit in select patients with alcoholic hepatitis, its use remains heterogeneous worldwide due to lack of uniform selection criteria. Over the last decade, several therapeutic targets have evolved of promise with ongoing clinical trials in patients with cirrhosis and alcoholic hepatitis. Even with availability of effective medical therapies for alcohol-associated liver disease, long-term outcome depends on abstinence from alcohol use in any spectrum of alcohol-associated liver disease. However, alcohol use disorder treatment remains underutilized due to several barriers even in patients with advanced disease. There is an urgent unmet need to implement and promote integrated multidisciplinary care model with hepatologists and addiction experts to provide comprehensive management for these patients. In this review, we will discuss newer therapies targeting liver disease and therapies targeting alcohol use disorder in patients with alcohol-associated liver disease. [ABSTRACT FROM AUTHOR]

• Acute alcohol intoxication is a harmful and potentially life-threatening condition secondary to the intake of large amounts of alcohol. • Clinical manifestations include behavioural and neurological symptoms, respiratory depression, coma and cardiac arrest. • Clinical stabilization and support of vital functions represent the cornerstone of the treatment. • Metadoxine represents a useful drug to increase ethanol metabolism and elimination. • Acute Alcohol Intoxication could represent a sentinel event of an underlying alcohol use disorder, requiring a multidisciplinary approach for reaching long term alcohol abstinence. Acute alcohol intoxication (AAI) is a harmful clinical condition, potentially life-threatening, secondary to the intake of large amounts of alcohol. Clinical manifestations of AAI are characterized by behavioural and neurological symptoms, even if its effects involve several organs and apparatus. Moreover, severe alcohol intoxication can produce a global neurological impairment leading to autonomic dysfunction, respiratory depression, coma and cardiac arrest. The evaluation of blood alcohol concentrations (BAC) is useful to confirm the suspicion of intoxication, both for clinical and legal reasons. Most of patients with AAI are referred to Emergency Departments due to behavioural, social, traumatic or clinical complications. Patient's stabilization is the first step in the management of AAI, in order to support vital functions and to prevent complications. Metadoxine represents a useful drug to increase ethanol metabolism and elimination. Given that AAI could represent a sentinel event of chronic alcohol abuse, patients presenting with acute intoxication should be screened for the presence of an underlying alcohol use disorder and referred to and an alcohol addiction unit to start a multidisciplinary treatment to achieve long term alcohol abstinence. The present review will focus on clinical features, diagnostic criteria and treatment strategies of AAI. [Display omitted] [ABSTRACT FROM AUTHOR]

In alcohol-associated hepatitis (AH), inflammation and neutrophil counts correlate with poor clinical outcomes. Here, we investigated how neutrophils contribute to liver damage in AH. We isolated blood neutrophils from individuals with AH to examine neutrophil extracellular traps (NETs) and performed RNA sequencing to explore their unique characteristics. We observed a significant increase in NET production in AH. We also observed a unique low-density neutrophil (LDN) population in individuals with AH and alcohol-fed mice that was not present in healthy controls. Transcriptome analysis of peripheral LDNs and high-density neutrophils (HDNs) from individuals with AH revealed that LDNs exhibit a functionally exhausted phenotype, while HDNs are activated. Indeed, AH HDNs exhibited increased resting reactive oxygen species (ROS) production and produced more ROS upon lipopolysaccharide stimulation than control HDNs, whereas AH LDNs failed to respond to lipopolysaccharide. We show that LDNs are generated from HDNs after alcohol-induced NET release in vitro , and this LDN subset has decreased functionality, including reduced phagocytic capacity. Moreover, LDNs showed reduced homing capacity and clearance by macrophage efferocytosis; therefore, dysfunctional neutrophils could remain in the circulation and liver. Depletion of both HDNs and LDNs in vivo prevented alcohol-induced NET production and liver damage in mice. Granulocyte-colony stimulating factor treatment also ameliorated alcohol-induced liver injury in mice. Neutrophils contribute to liver damage through increased NET formation which increases defective LDNs in AH. Alcohol induces phenotypic changes in neutrophils; HDNs are activated whereas LDNs are defective. Our findings provide mechanistic insights that could guide the development of therapeutic interventions for AH. In this study we discovered heterogeneity of neutrophils in alcohol-associated hepatitis, including high-density and low-density neutrophils that show hyper-activated or exhausted transcriptomic profiles, respectively. We found that alcohol induces neutrophil extracellular trap (NET) formation, which contributes to liver damage. NET release by high-density neutrophils resulted in low-density neutrophils that reside in the liver and escape clean-up by macrophages. Our findings help to understand the opposing neutrophil phenotypes observed in individuals with alcohol-associated hepatitis and provide mechanistic insights that could guide therapeutic strategies targeting neutrophils. [Display omitted] • Alcohol directly induces neutrophil extracellular trap formation in neutrophils. • Alcohol-induced neutrophil extracellular trap production increases low-density neutrophils in AH. • Low-density neutrophils in AH have a defective phenotype and exhibit reduced homing and clearance. • High-density neutrophils in AH have an activated phenotype. [ABSTRACT FROM AUTHOR]

Alcohol abuse can lead to alcoholic hepatitis (AH), a worldwide public health issue with high morbidity and mortality. Here, we identified apolipoprotein A-IV (APOA4) as a biomarker and potential therapeutic target for AH. APOA4 expression was detected by Gene Expression Omnibus (GEO) databases, Immunohistochemistry, and qRT-PCR in AH. Bioinformatics Methods (protein–protein interaction (PPI) network, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and Gene Set Enrichment Analysis (GSEA) were used to show down-stream gene and pathways of APOA4 in AH. AML-12 cells were used to evaluate the biological function of APOA4 using an ELISA kit (AST, ALT, and IL-1β) and flow cytometry (ROS activity). Both in vivo and in vitro, APOA4 expression was significantly elevated in the AH model induced by alcohol (ETOH). AML-12 cell damage was specifically repaired by APOA4 deficiency, while AST, ALT, and IL-1β activity that was increased by ETOH (200 µmol, 12 h) were suppressed. APOA4 inhibition increased intracellular ROS induced by ETOH, which was detected by flow cytometry. Functional and PPI network analyses showed Fcgamma receptor (FCGR) and platelet activation signaling were potential downstream pathways. We identified CIDEC as a downstream gene of APOA4. The CIDEC AUC values for the ROC curves were 0.861. At the same time, APOA4 silencing downregulated the expression of CIDEC, whereas the knockdown of CIDEC did not influence the expression of APOA4 in AML-12 cells. Collectively, APOA4 regulates CIDEC expression and immune cell infiltration and may hold great potential as a biomarker and therapeutic target for AH. [ABSTRACT FROM AUTHOR]

Consumption of alcohol in excess leads to substantial medical, economic, and societal burdens. Approximately 5.3% of all global deaths may be attributed to alcohol consumption. Moreover, the burden of alcohol associated liver disease (ALD) accounts for 5.1% of all disease and injury worldwide. Alcohol use disorder (AUD) affects men more than women globally with significant years of life loss to disability in low, middle and well-developed countries. Precise data on global estimates of alcohol related steatosis, alcohol related hepatitis, and alcohol related cirrhosis have been challenging to obtain. In the United States (US), alcohol related steatosis has been estimated at 4.3% based on NHANES data which has remained stable over 14 years. However, alcohol-related fibrotic liver disease has increased over the same period. In those with AUD, the prevalence of alcohol related hepatitis has been estimated at 10–35%. Globally, the prevalence of alcohol-associated cirrhosis has been estimated at 23.6 million individuals for compensated cirrhosis and 2.46 million for those with decompensated cirrhosis. The contribution of ALD to global mortality and disease burden of liver related deaths is substantial. In 2016 liver disease related to AUD contributed to 50% of the estimated liver disease deaths for age groups 15 years and above. Data from the US report high cost burdens associated with those admitted with alcohol-related liver complications. Finally, the recent COVID-19 pandemic has been associated with marked increase in alcohol consumption worldwide and will likely increase the burden of ALD. [ABSTRACT FROM AUTHOR]

Alterations in the composition of the gut microbiota (dysbiosis) are observed in nutritional liver diseases, including non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) and have been shown to be associated with the severity of both. Editing the composition of the microbiota by fecal microbiota transfer or by application of probiotics or prebiotics/fiber in rodent models and human proof-of-concept trials of NAFLD and ALD have demonstrated its possible contribution to reducing the progression of liver damage. In this review, we address the role of a soluble fiber, pectin, in reducing the development of liver injury in NAFLD and ALD through its impact on gut bacteria. [ABSTRACT FROM AUTHOR]

Alcoholic hepatitis is a major health and economic burden worldwide. Glucocorticoids (GCs) are the only first-line drugs recommended to treat severe alcoholic hepatitis (sAH), with limited short-term efficacy and significant side effects. In this review, I summarize the major benefits and side effects of GC therapy in sAH and the potential underlying mechanisms. The review of the literature and data mining clearly indicate that the hepatic signaling of glucocorticoid receptor (GR) is markedly impaired in sAH patients. The impaired GR signaling causes hepatic down-regulation of genes essential for gluconeogenesis, lipid catabolism, cytoprotection, and anti-inflammation in sAH patients. The efficacy of GCs in sAH may be compromised by GC resistance and/or GC's extrahepatic side effects, particularly the side effects of intestinal epithelial GR on gut permeability and inflammation in AH. Prednisolone, a major GC used for sAH, activates both the GR and mineralocorticoid receptor (MR). When GC non-responsiveness occurs in sAH patients, the activation of MR by prednisolone might increase the risk of alcohol abuse, liver fibrosis, and acute kidney injury. To improve the GC therapy of sAH, the effort should be focused on developing the biomarker(s) for GC responsiveness, liver-targeting GR agonists, and strategies to overcome GC non-responsiveness and prevent alcohol relapse in sAH patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: Higher prevalence of alcohol-related gastrointestinal (GI) and liver diseases (ARGLDs) were anecdotally reported during the COVID-19 pandemic, but little published evidence exists. METHODS: A healthcare system audit of inpatient GI consults was performed during the pandemic's lockdown phase (3/23/2020-5/10/2020, n=558) and reopening phase (6/1/2020-7/19/2020, n=711) with comparison to those timeframes in 2019. RESULTS: Consult volume decreased by 27.7% during the lockdown, but the proportion of ARGLDs increased by 59.6% (p=0.03). This trend continued during reopening, with potentially more severe disease as more patients required endoscopic intervention. Patients with alcoholic hepatitis during reopening were younger compared to the lockdown. CONCLUSIONS: Our study demonstrates increased prevalence and severity of ARGLDs amongst younger individuals during the COVID-19 pandemic. This increase started during the lockdown but worsened despite relaxation of restrictions. Systems to increase screening for and treatment of alcohol use disorder as society recovers from the pandemic remain imperative. [ABSTRACT FROM AUTHOR]

Background: Therapeutic plasma exchange (TPE) is a well‐established treatment modality in acute liver failure patients, but its efficacy in treating acute on chronic liver failure (ACLF) patients is yet to be established. Aim: To assess the efficacy and safety of TPE in patients with alcohol‐associated ACLF who were nonresponders to standard medical treatment (SMT) and without immediate prospects for liver transplantation. Methods: Twenty‐eight alcohol‐related ACLF (grade II) patients (14 cases and 14 controls) were enrolled in the study. Cases underwent standard volume TPE along with SMT while the controls were on SMT alone. The change (baseline to day 10) in laboratory parameters, cytokine concentrations, clinical severity scores along with 30 and 90 day mortality rates were noted and compared between the two groups. The adverse events (AEs) were noted in the groups and analyzed. Results: A total of 51 TPE procedures were performed in 14 patients (average of 3.62 procedures/patient). TPE was effective in reduction of serum bilirubin, ammonia, activated partial thromboplastin time, prothrombin time, international normalized ratio, and severity scores (ACLF Research Consortium, Maddrey's discriminant function, and model for end‐stage liver disease) (P <.05). There was no significant difference in the reduction of serum interleukin‐6 (IL‐6), IL‐10, and tumor necrosis factor‐α concentrations among cases. Among the cases who received the complete TPE interventions, 30‐ and 90‐day mortality rates were lower in the cases as compared to controls albeit only the 90‐day mortality was significantly different. Procedure‐related AEs was observed in 2% of procedures. Conclusion: TPE is an effective and well‐tolerated bridge therapy in patients with alcohol‐associated ACLF of moderate severity not improving on SMT and without immediate prospects for liver transplantation. [ABSTRACT FROM AUTHOR]

Puerarin, a bioactive flavone compound isolated from Pueraria (Wild.), provides hepatoprotection by anti-inflammatory, anti-alcoholism, and regulating mechanistic target of rapamycin (mTOR). Building evidence suggests that the activation of mTOR reduces liver injuries associated with alcohol consumption and metabolism. However, the poor water solubility, low bioavailability, and short half-life of puerarin hinder its clinical application. The utility of mesoporous silicon nanoparticles (MSNs) can improve traditional Chinese medicine limitations. Stober methods were used to fabricate MSNs@Pue, and the size, zeta potentials and drug encapsulation efficiency were characterized by a series of analytical methods. IVIS Imaging System demonstrated liver-targeted bio-distribution, and then high-throughput sequencing, immunoproteomics and ultrastructure methods indicated autophagy related protective mechanism, followed by curative effect evaluation for the treatment efficacy. An acute-on chronic ethanol-drinking according to Gao-binge model induced alcoholic hepatitis (AH) pathology and resulted in hepatic hyper-autophagy, which was improved with MSNs@Pue administration (puerarin: 30 mM, 42 mg/kg; intravenously [i.v.]). Ethanol-fed mice were found to have increased expression of autophagy-related proteins (Atg3, Atg7, LC3 and p62). In contrast, MSNs@Pue administration significantly decreased the expression of these proteins and alleviated fatty droplets infiltration in damaged liver. Furthermore, acute-on-chronic ethanol feeding also resulted in the activiation of ERK activation and mTOR expression, which were reversed with MSNs@Pue administration and better than the usage of puerarin alone. Results point to MSNs@Pue mediated ERK/mTOR signaling pathway activation as a possible protective strategy to improve AH, which provides a strategy and evidence for treating liver disease using an MSN delivery system. [ABSTRACT FROM AUTHOR]

Alcoholic hepatitis (AH) is the most severe form of alcoholic liver disease for which there is no efficacious treatment aiding most patients. AH manifests differently in individuals, with some patients showing debilitating symptoms more so than others. Previous studies showed significant metabolic dysregulation associated with AH. Therefore, we sought to analyze how the activity of metabolic pathways differed in the liver of patients with varying degrees of AH severity. We utilized a genome-scale metabolic modeling approach that allowed for integration of a generic human cellular metabolic model with specific RNA-seq data corresponding to healthy and multiple liver disease states to predict the metabolic fluxes within each disease state. Additionally, we performed a systems-level analysis of the transcriptomic data and predicted metabolic flux data to identify the regulatory and functional differences in liver metabolism with increasing severity of AH. Our results provide unique insights into the sequential dysregulation of the solute transport mechanisms underlying the glutathione metabolic pathway with increasing AH disease severity. We propose targeting of the solute transporters in the glutathione pathway to mimic the flux activity of the healthy liver state as a potential therapeutic intervention for AH. [ABSTRACT FROM AUTHOR]

Background and aim: Severe alcoholic hepatitis (SAH), the most florid form of alcohol-related liver disease (ALD), has a mortality rate of 16% at 28 days. The angiopoietin-Tie 2 system regulates angiogenesis and inflammation, both of which are implicated in the pathogenesis of ALD. This study examined plasma and hepatic gene expression of angiopoietin 1 (ANG1) and angiopoietin 2 (ANG2) in patients with SAH and ALD and investigated their roles as prognostic biomarkers. Methods: A case-control study was performed measuring plasma levels of ANG1 and ANG2 by enzyme-linked immunosorbent assay (ELISA) from 30 patients with SAH (Maddrey's discriminant function ≥32), 32 patients with ALD cirrhosis and 15 healthy controls (HC). RNA sequencing for ANG1, ANG2, TIE1 (codes for Tie1 receptor) and TEK (codes for Tie2 receptor) gene expression from a separate cohort study of 79 patients was also performed. Results: Plasma levels of ANG1 were lower (P = 0.010) and ANG2 were higher (P

Alcoholic hepatitis (AH) is a rapidly progressing and severe stage of alcoholic liver disease, presenting a grim prognosis. Extensive research has elucidated several underlying mechanisms that contribute to the development of AH, including metabolic alterations, immune stimulation, and intestinal dysbiosis. These pathological changes intricately intertwine during the progression of AH. Notably, recent studies have increasingly highlighted the pivotal role of alterations in the intestinal microbiota in the pathogenesis of AH. Consequently, future investigations should place significant emphasis on exploring the dynamics of intestinal microbiota. In this comprehensive review, we consolidate the primary causes of AH while underscoring the influence of gut microbes. Furthermore, by examining AH treatment strategies, we delineate the potential therapeutic value of interventions targeting the gut microbiota. Given the existing limitations in AH treatment options, we anticipate that this review will contribute to forthcoming research endeavors aimed at advancing AH treatment modalities.