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Background/Objectives: Bacterial infections (BI) are a major cause of mortality in patients with alcohol-associated hepatitis (AH); however, only a few studies have investigated BI in AH in the last decade. Therefore, we aimed to assess the features and outcomes of BI in patients with AH. Methods: This observational descriptive study included patients with AH admitted to a tertiary academic hospital between 2016 and 2021. Clinical and complete microbiological data were recorded and complications, including acute-on-chronic liver failure (ACLF), and mortality over 90-days were compared between infected and noninfected patients. Results: Overall, 115 patients with AH were recruited and 75 had severe AH; among them, 66 started corticosteroid treatment. We identified 69 cases of BI in 44 patients; the incidence of BI upon hospital discharge was 32.2%, which reached 38.2% at 90 days. The predominant infection site was the chest (35%). Among the identified bacteria (52.1%), half were gram positive and half gram negative. A low rate of multidrug-resistant bacteria (14%) was also noted. Infected patients during hospitalization (n = 37) exhibited higher rates of hepatic decompensation and ACLF (p = 0.001) and lower survival (81.8% vs. 95.8%, p = 0.015) than did noninfected patients (n = 78). In-hospital infected patients (n = 22) exhibited worse survival (72.7%) than did those infected upon admission (93.3%) or noninfected patients (94.9%) (p = 0.009). Corticosteroid-treated patients displayed a nonsignificant increase in the total number of BI; however, without greater mortality. Conclusions: BI were common in our cohort of patients with AH. Patients with in-hospital infections commonly experienced serious complications, including high ACLF and death rates. Infections diagnosed upon admission were treated without affecting survival. [ABSTRACT FROM AUTHOR]

This report describes the clinical course of a 41 year-old African woman who presented with an episode of acute alcoholic pancreatitis followed next by severe alcoholic hepatitis (SAH). Initially admitted for pancreatitis, the patient responded promptly to comprehensive treatment with strict abstinence from alcohol. However, remarkable elevations in white blood cell count to 44,000/µL and total bilirubin level to 12.4 mg/dL were observed 5–7 weeks later. Contrast-enhanced computed tomography revealed rapidly progressing hepatosplenomegaly. Histological analysis of a liver biopsy detected ballooned hepatocytes with Mallory–Denk bodies and significant neutrophilic infiltration in the hepatic parenchyma, which confirmed the diagnosis of SAH. The patient's hepatosplenomegaly and overall condition improved with supportive care alone. The reported case reveals the unexpected fact that SAH can develop after alcoholic acute pancreatitis. [ABSTRACT FROM AUTHOR]

Alcohol-associated liver disease is highly prevalent worldwide, with alcohol-associated hepatitis as a severe form characterized by substantial morbidity, mortality, and economic burden. Gut bacterial dysbiosis has been linked to progression of alcohol-associated hepatitis. Fecal cytolysin secreted by the pathobiont Enterococcus faecalis (E. faecalis) is associated with increased mortality in patients with alcohol-associated hepatitis. Although gelatinase is considered a virulence factor in E. faecalis, its prevalence and impact on alcohol-associated hepatitis patient outcomes remains unclear. In this study, 20 out of 65 (30.8%) patients with alcohol-associated hepatitis tested positive for gelatinase in their stool. There were no significant differences in 30-day and 90-day mortality between gelatinase-positive and gelatinase-negative patients (p=0.97 and p=0.48, respectively). Fecal gelatinase had a low discriminative ability for 30-day mortality (area under the curve [AUC] 0.50 vs fibrosis-4 Index (FIB-4) 0.75) and 90-day mortality compared with other established liver disease markers (AUC 0.57 vs FIB-4 0.79 or ‘age, serum bilirubin, INR, and serum creatinine’ (ABIC) score 0.78). Furthermore, fecal gelatinase was not an important feature for 30-day or 90-day mortality per random forest analysis. Finally, gelatinase-positive patients with alcohol-associated hepatitis did not exhibit more severe liver disease compared with gelatinase-negative patients. In conclusion, fecal gelatinase does not predict mortality or disease severity in patients with alcohol-associated hepatitis from our cohort.

Harmful alcohol consumption is one of the leading risk factors for global disease burden and injury condition, causing death and disability early in life, with over 3 million deaths worldwide every year. Alcoholic hepatitis (AH) is a clinical syndrome characterized by hepatic failure with recent onset of jaundice, consequence of a heavy chronic alcohol drinking. The disease severity ranges from mild to severe cases, with high short-term mortality. Individual variety regarding disease outcome and therapeutic response complicates the prognosis stratification. Thus, novel parameters and continuously sought for a better disease outcome assessment.

Introduction: Alcoholic hepatitis (AH) is a serious complication of alcohol consumption with high morbidity and mortality, particularly in the United States where alcohol-related liver diseases rank as one of the leading causes of preventable death. Our study aims to analyze the morbidity and mortality of AH across racial groups and project hospitalization trends up to 2028, thereby informing public health initiatives. Methods: We conducted a cross-sectional study utilizing data from the Nationwide Inpatient Sample (NIS) spanning 2012 to 2021. The study population comprised hospitalizations identified using specific ICD-9-CM and ICD-10-CM codes for AH. We assessed hospitalizations, in-hospital mortality rates, length of stay (LOS), and morbidities related to alcoholic hepatitis adjusting for sociodemographic factors and hospital characteristics. Statistical analyses were performed using Stata and R software, employing logistic and linear regression analyses, and SARIMA models for forecasting. Results: Our results indicated a predominantly White cohort (68%), with a notable increase in AH hospitalizations among Hispanics (129.1% from 2012 to 2021). Racial disparities were observed in inpatient mortality, liver transplant accessibility, and the occurrence of in-hospital complications. The study forecasts a continued rise in hospitalizations across all racial groups, with Hispanics experiencing the sharpest increase. Conclusion: Our study reveals a disproportionate rise in the AH burden among Hispanics with projections indicating a persistent upward trend through 2028. These findings highlight the need for targeted public health strategies and improved healthcare access to mitigate the increasing AH burden and address disparities in care and outcomes. [ABSTRACT FROM AUTHOR]

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Abstract Background Mechanisms and consequences of Gasdermin D (GSDMD) activation in alcoholic hepatitis (AH) are unclear. In the present study, we investigated whether GSDMD induces hepatocyte pyroptosis by regulating mitochondrial dysfunction in AH. Results Liver damage in AH mice was assessed by HE staining, serum levels of AST, ALT, TC, and TG. The levels of IL-1β, IL-18, LDH, inflammasome-associated proteins and hepatocyte death were assessed to determine pyroptosis. Mitochondrial dysfunction was assessed through various parameters including mitochondrial DNA (mtDNA) levels, ROS generation, mitochondrial membrane potential, ATP contents, levels of mitochondrial function-related proteins and morphological changes of mitochondria. AH induced gasdermin D (GSDMD) activation, leading to increased protein expression of N-terminal GSDMD (GSDMD-N), NLRP3, and Caspase 11 in liver tissues. Downregulation of GSDMD alleviated alcohol-induced hepatocyte pyroptosis. Alcohol also causes mitochondrial dysfunction in hepatocytes in AH, which was improved by inhibiting GSDMD. Furthermore, enhancing mitochondrial function suppressed alcohol-induced hepatocyte pyroptosis. Further, knockdown of GSDMD or dynamin-related protein 1 (Drp1) improved AH-induced liver injury, accompanied by a decrease in hepatocyte pyroptosis. Conclusion GSDMD induces hepatocyte pyroptosis by modulating mitochondrial dysfunction during AH-induced inflammation and liver injury. These findings may pave the way to develop new therapeutic treatments for AH.

In this research, the influence of hirsutidin on mice with alcoholic liver disease was examined. A total of 30 mice were randomly allocated to five groups (n = 6): Normal control group, Ethanol (EtOH) control group, hirsutidin-10, hirsutidin-20, and hirsutidin-20 per se for 4-week. Furthermore, 1 h after the last dosage of the treatment, 5 mL/kg (i.p.) EtOH (56%) was injected to cause hepatic injury. After 5 h of EtOH administration, blood samples were taken, and then the liver was excised for biochemical analysis. Hirsutidin treatment restored the biochemical changes induced by EtOH: serum levels of liver function tests, lipid profile, blood urea nitrogen, antioxidants levels, malondialdehyde, and cytokines. Hirsutidin supplementation also significantly decreased the histopathological abnormalities in EtOH-induced mice. In the present study, hirsutidin was found to have therapeutic potential for the treatment of alcoholic liver disease. Hirsutidin prevented ethanol-induced biochemical and histopathological alterations in the liver, suggesting its hepatoprotective effect.

Background & aimsSrc 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.MethodsLiver 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.ResultsShc 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.ConclusionsAlcohol 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.

BackgroundIn trials conducted in India, recombinant granulocyte colony stimulating factor (GCSF) improved survival in alcohol-associated hepatitis (AH). The aim of this trial was to determine the safety and efficacy of pegfilgrastim, a long-acting recombinant GCSF, in patients with AH in the United States.MethodsThis prospective, randomized, open label trial conducted between March 2017 and March 2020 randomized patients with a clinical diagnosis of AH and a Maddrey discriminant function score ≥32 to standard of care (SOC) or SOC+pegfilgrastim (0.6 mg subcutaneously) on Day 1 and Day 8 (clinicaltrials.gov NCT02776059). SOC was 28 days of either pentoxifylline or prednisolone, as determined by the patient's primary physician. The second injection of pegfilgrastim was not administered if the white blood cell count exceeded 30,000/mm3 on Day 8. Primary outcome was survival at Day 90. Secondary outcomes included the incidence of acute kidney injury (AKI), hepatorenal syndrome (HRS), hepatic encephalopathy, or infections.FindingsThe study was terminated early due to COVID19 pandemic. Eighteen patients were randomized to SOC and 16 to SOC+pegfilgrastim. All patients received prednisolone as SOC. Nine patients failed to receive a second dose of pegfilgrastin due to WBC > 30,000/mm3 on Day 8. Survival at 90 days was similar in both groups (SOC: 0.83 [95% confidence interval [CI]: 0.57-0.94] vs. pegfilgrastim: 0.73 [95% CI: 0.44-0.89]; p > 0.05; CI for difference: -0.18-0.38). The incidences of AKI, HRS, hepatic encephalopathy, and infections were similar in both treatment arms and there were no serious adverse events attributed to pegfilgrastim.InterpretationThis phase II trial found no survival benefit at 90 days among subjects with AH who received pegfilgrastim+prednisolone compared with subjects receiving prednisolone alone.Fundingwas provided by the United States National Institutes of Health and National Institute on Alcohol Abuse and Alcoholism U01-AA021886 and U01-AA021884.

Larsucosterol, a potent endogenous epigenetic regulator, has been reported to play a significant role in lipid metabolism, inflammatory responses, and cell survival. The administration of larsucosterol has demonstrated a reduction in lipid accumulation within hepatocytes and the attenuation of inflammatory responses induced by lipopolysaccharide (LPS) and TNFα in macrophages, alleviating LPS- and acetaminophen (ATMP)-induced multiple organ injury, and decreasing mortalities in animal models. Results from phase 1 and 2 clinical trials have shown that larsucosterol has potential as a biomedicine for the treatment of acute and chronic liver diseases. Recent evidence suggests that larsucosterol is a promising candidate for treating alcohol-associated hepatitis with positive results from a phase 2a clinical trial, and for metabolic dysfunction-associated steatohepatitis (MASH) from a phase 1b clinical trial. In this review, we present a culmination of our recent research efforts spanning two decades. We summarize the discovery, physiological and pharmacological mechanisms, and clinical applications of larsucosterol. Furthermore, we elucidate the pathophysiological pathways of metabolic dysfunction-associated steatotic liver diseases (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), and acute liver injuries. A central focus of the review is the exploration of the therapeutic potential of larsucosterol in treating life-threatening conditions, including acetaminophen overdose, endotoxin shock, MASLD, MASH, hepatectomy, and alcoholic hepatitis. [ABSTRACT FROM AUTHOR]

Summary: Background: Alcohol‐associated hepatitis (AH) is a severe inflammatory form of alcohol‐associated liver disease (ALD) that carries a high mortality rate. Early liver transplantation for severe AH is increasingly available. However, specific criteria for referral and selection remain a subject of debate. Aims: To provide a narrative review of the natural history, diagnostic criteria and indications for referral for early liver transplantation for severe AH. Methods: We searched PubMed for articles published through August 2023. Key search terms were 'alcoholic hepatitis,' 'alcohol‐associated hepatitis,' 'abstinence,' 'alcohol relapse,' and 'liver transplantation.' Results: Previously, a six‐month period of alcohol abstinence was required before patients with ALD were considered for liver transplantation. However, studies in recent years have demonstrated that, among carefully selected patients, patients who received early transplants have much higher survival rates than patients with similarly severe disease who did not undergo transplants (77% vs. 23%). Despite these successes, early liver transplantation remains controversial, as these patients have typically not undergone treatment for alcohol use disorder, with the ensuing risk of returning to alcohol use. Conclusions: While early liver transplantation for AH has survival benefits, many patients would not have received treatment for alcohol use disorder. An integrated approach to evaluating candidacy for early liver transplantation is needed. [ABSTRACT FROM AUTHOR]

Severe alcohol-associated hepatitis (SAH) is associated with high 90-day mortality. Glucocorticoid therapy for 28 days improves 30- but not 90-day survival. We assessed the efficacy and safety of a combination of anakinra, an IL-1 antagonist, plus zinc (A+Z) compared to prednisone using the Day-7 Lille score as a stopping rule in patients with SAH. In this phase IIb double-blind randomized trial in adults with SAH and MELD scores of 20-35, participants were randomized to receive either daily anakinra 100 mg subcutaneously for 14 days plus daily zinc sulfate 220 mg orally for 90 days, or daily prednisone 40 mg orally for 30 days. Prednisone or prednisone placebo was stopped if Day-7 Lille score was >0.45. All study drugs were stopped for uncontrolled infection or ≥5 point increase in MELD score. The primary endpoint was overall survival at 90 days. Seventy-three participants were randomized to prednisone and 74 to A+Z. The trial was stopped early after a prespecified interim analysis showed prednisone was associated with higher 90-day overall survival (90% vs. 70%; hazard ratio for death = 0.34, 95% CI 0.14–0.83, p = 0.018) and transplant-free survival (88% vs. 64%; hazard ratio for transplant or death = 0.30, 95% CI 0.13–0.69, p = 0.004) than A+Z. Acute kidney injury was more frequent with A+Z (45%) than prednisone (22%) (p = 0.001), but rates of infection were similar (31% in A+Z vs. 27% in prednisone, p = 0.389). Participants with SAH treated with prednisone using the Day-7 Lille score as a stopping rule had significantly higher overall and transplant-free 90-day survival and lower incidence of acute kidney injury than those treated with A+Z. There is no approved treatment for severe alcohol-associated hepatitis (SAH). In this double-blind randomized trial, patients with SAH treated with prednisone using the Lille stopping rule on Day 7 had higher 90-day overall and transplant-free survival and lower rates of acute kidney injury compared to patients treated with a combination of anakinra and zinc. The data support continued use of glucocorticoids for patients with SAH, with treatment discontinuation for those with a Lille score >0.45 on Day 7. NCT04072822. [Display omitted] • Severe alcohol-associated hepatitis is associated with high short-term mortality. • 147 patients with SAH (MELD ≥20) were enrolled in a double-blind randomized trial. • Participants received prednisone or anakinra plus zinc. • Day-7 Lille score >0.45 was a stopping rule for prednisone/prednisone placebo. • Prednisone resulted in better overall and transplant-free survival at 90 days. [ABSTRACT FROM AUTHOR]

Background: Previously, we demonstrated that Spp1−/− mice exhibit a greater susceptibility to alcohol‐induced liver injury than wild‐type (WT) mice. Notably, alcohol triggers the expression of osteopontin (encoded by SPP1) in hepatocytes. However, the specific role of hepatocyte‐derived SPP1 in either mitigating or exacerbating alcohol‐associated liver disease (AALD) has yet to be elucidated. We hypothesized that hepatocyte‐derived SPP1 plays a role in AALD by modulating the regulation of steatosis. Methods: We analyzed hepatic SPP1 expression using four publicly available datasets from patients with alcoholic hepatitis (AH). Additionally, we examined SPP1 expression in the livers of WT mice subjected to either a control or ethanol Lieber‐DeCarli (LDC) diet for 6 weeks. We compared the relationship between SPP1 expression and significantly dysregulated genes in AH with controls using correlation and enrichment analyses. To investigate the specific impact of hepatocyte‐derived SPP1, we generated hepatocyte‐specific Spp1 knock‐out (Spp1ΔHep) mice and subjected them to either a control or ethanol Lieber‐DeCarli diet for 6 weeks. Results: Alcohol induced hepatic SPP1 expression in both humans and mice. Our analysis, focusing on genes correlated with SPP1, revealed an enrichment of fatty acid oxidation (FAO) in three datasets, and peroxisome proliferator‐activated receptor signaling in one dataset. Notably, FAO genes correlating with SPP1 were downregulated in patients with AH. Ethanol‐fed WT mice exhibited higher serum‐free fatty acids (FFAs), adipose tissue lipolysis, and hepatic fatty acid (FA) transporters. In contrast, ethanol‐fed Spp1ΔHep mice displayed lower liver triglycerides, FFAs, and serum alanine transaminase and greater FAO gene expression than WT mice, indicating a protective effect against AALD. Primary hepatocytes from Spp1∆Hep mice exhibited heightened expression of genes encoding proteins involved in FAO. Conclusions: Alcohol induces the expression of SPP1 in hepatocytes, leading to impaired FAO and contributing to the development of AALD. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the regulatory function of the non-coding microRNA-155 (miR-155) and suppressor of cytokine signaling 1 (SOCS1) in alcoholic hepatitis (AH) and its potential mechanism associated with the mitogen-activated protein kinase (MAPK) signaling pathway. Levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB), total bilirubin (TBIL), malondialdehyde (MDA), and superoxide dismutase (SOD) were measured in a rat model of AH. The biological prediction website microRNA.org and dual-luciferase reporter gene assay were used to identify whether SOCS1 was a direct target of miR-155, and the effects of miR-155 and SOCS1 on the viability, cycle progression, and apoptosis of hepatic stellate cells were assessed using RT-qPCR, Western blot assay, MTT assay, Annexin V/PI double staining, and PI single staining. The levels of ALT, AST, MDA, and TBIL and the liver cell morphology were all prominently changed in AH model rats. miR-155 suppressed SOCS1 by specifically binding to SOCS1-3'-UTR to activate the MAPK signaling pathway. SOCS1 had low expression while miR-155 was highly expressed in AH rats. miR-155 promoted hepatic stellate cell viability and cycle progression and reduced cell apoptosis by silencing SOCS1. Together, we find that silenced miR-155 could upregulate SOCS1 and inactivate the MAPK signaling pathway, thereby inhibiting the proliferation of alcoholic hepatic stellate cells and promoting cell apoptosis. [ABSTRACT FROM AUTHOR]

Background & aims: Few studies have investigated the prognosis of patients with non-severe alcoholic hepatitis (Non-SAH). The study aimed to develop a new prognostic model for patients with especially Non-SAH. Methods: We extracted 316 hospitalized patients with alcoholic cirrhosis without severe alcoholic hepatitis, defined as Maddrey's discriminant function score lower than 32, from the retrospective Korean Acute-on-Chronic Liver Failure (KACLiF) cohort to develop a new prognostic model (training set), and validated it in 419 patients from the prospective KACLiF cohort (validation set). Prognostic factors for death and liver transplantation were analyzed to construct a prognostic model. Results: Twenty-one and 24 patients died within 6 months in both sets, respectively. In the training set, the highest area under the curve (AUC) of conventional prognostic models was 0.765, 0.732, and 0.684 for 1-, 3-, and 6-month mortality, respectively. Refractory ascites, vasopressor use, and hyponatremia were independently associated with mortality of cirrhotic patients with Non-SAH. The new model consisted of four variables: past deterioration, neutrophil proportion > 70%, Na < 128 mmol/L, and vasopressor use. It showed the highest accuracy for short-term mortality in the training and validation sets (0.803 and 0.786; 0.797 and 0.776; and 0.789 and 0.721 for 1-, 3-, and 6-month mortality, respectively). Conclusion: There is a group of patients with high risk among those classified as Non-SAH. The new model will help stratifying cirrhotic patients with Non-SAH more accurately in terms of prognosis. The patients with high Non-SAH score need to monitor closely and might be considered for preemptive liver transplantation. Trial regestration: ClinicalTrials.gov identifier: NCT02650011. [ABSTRACT FROM AUTHOR]

Background: Mechanisms and consequences of Gasdermin D (GSDMD) activation in alcoholic hepatitis (AH) are unclear. In the present study, we investigated whether GSDMD induces hepatocyte pyroptosis by regulating mitochondrial dysfunction in AH. Results: Liver damage in AH mice was assessed by HE staining, serum levels of AST, ALT, TC, and TG. The levels of IL-1β, IL-18, LDH, inflammasome-associated proteins and hepatocyte death were assessed to determine pyroptosis. Mitochondrial dysfunction was assessed through various parameters including mitochondrial DNA (mtDNA) levels, ROS generation, mitochondrial membrane potential, ATP contents, levels of mitochondrial function-related proteins and morphological changes of mitochondria. AH induced gasdermin D (GSDMD) activation, leading to increased protein expression of N-terminal GSDMD (GSDMD-N), NLRP3, and Caspase 11 in liver tissues. Downregulation of GSDMD alleviated alcohol-induced hepatocyte pyroptosis. Alcohol also causes mitochondrial dysfunction in hepatocytes in AH, which was improved by inhibiting GSDMD. Furthermore, enhancing mitochondrial function suppressed alcohol-induced hepatocyte pyroptosis. Further, knockdown of GSDMD or dynamin-related protein 1 (Drp1) improved AH-induced liver injury, accompanied by a decrease in hepatocyte pyroptosis. Conclusion: GSDMD induces hepatocyte pyroptosis by modulating mitochondrial dysfunction during AH-induced inflammation and liver injury. These findings may pave the way to develop new therapeutic treatments for AH. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Hepatorenal syndrome (HRS) frequently complicates alcoholic hepatitis (AH) and portends poor survival in this population. Published literature indicates mixed benefits from renal replacement therapy (RRT) for HRS refractory to medical management. Therefore, we sought to assess the utilization of RRT in AH and clinical outcomes at a national level. Methods: Using the International Classification of Diseases, Tenth Revision (ICD‐10) codes, we identified adult patients with AH with a coexisting diagnosis of HRS from the National Readmission Database 2016 through 2019. Mortality, morbidity, and resource utilization were compared. We compared proportions using the Fisher exact test and computed adjusted P‐values based on multivariate regression analysis. Analyses were performed using Stata, version 14.2, considering a two‐sided P < 0.05 as statistically significant. Results: A total of 73 203 patients with AH were included in the analysis (mean age 46.2 years). A total of 3620 individuals had HRS diagnosis (5%), of which 14.7% (n: 532) underwent RRT. HRS patients receiving RRT had a higher mortality rate than those who did not (adjusted odds ratio [aOR] 1.8, 95% confidence interval [CI]: 1.3–2.6, P: 0.01), along with higher resource utilization. Only those patients with HRS who underwent liver transplantation (LT) experienced a mortality reduction (24.4% for those not receiving RRTs and 36.5% for those receiving RRT). Conclusions: RRT is associated with higher mortality and morbidity when offered to patients with AH and HRS, who do not undergo LT. Therefore, our results suggest careful selection of AH patients when deciding to initiate RRT for HRS. [ABSTRACT FROM AUTHOR]

Introduction: Alcoholic hepatitis is a major health problem which carries a high mortality despite treatment. Predicting severity of disease is of utmost importance to avoid overzealous and unnecessary treatment with steroids in each and every case. Maddrey’s discriminant function (DF) may not always be reliable in predicting such prognosis. Aim of the Study: To observe the predictive ability of Glasgow alcoholic hepatitis score (GAHS), age, bilirubin, international normalized ratio (INR) and creatinine (ABIC) score, model for end stage liver disease (MELD) score, and Lille’s score in determining the prognosis in severe alcoholic hepatitis. Materials and Methods: Patients of severe alcoholic hepatitis were enrolled in this study as per inclusion and exclusion criteria and a DF score of >32. Once the decision to initiate corticosteroids was made, DF scores, MELD scores, GAHS scores, and ABIC scores were calculated on the day on initiation of therapy. On day 7, patients were re‑assessed and Lille score was calculated in addition. Follow‑up was obtained on repeat out‑patient visit or telephonically after every 2 weeks till 90 days or till mortality, whichever occurred first. Statistical Analysis: The scores were compared among the survival and mortality groups to see association between mortality and severity of scores using Chi‑square test of significance. Cut‑offs providing a composite of best sensitivity, specificity, negative predictive value, and positive predictive value were derived on the basis of data of our study. P value of ≤ 0.05 was taken as a cut‑off for significance. Results: Our study comprised 30 patients with severe alcoholic hepatitis. At the end of 90‑day follow‑up, 23 patients survived with 7 (23%) mortalities because of liver failure and sepsis. On day 7, barring the ABIC score (0.713), the areas under curve of all scores were above 0.8 and were hence of comparable efficacy. Lille score performed the best at assessing treatment response but had the limitation of not being applicable at day 1. Conclusion: Severe alcoholic hepatitis carries a bad prognosis. Cut‑offs of DF and MELD need to be raised, whereas they need to be lowered in the case of GAHS, ABIC, and Lille score to improve the predictive value of score. Steroid‑treated patients should be evaluated preferably with Lille score for a better prediction of survival. [ABSTRACT FROM AUTHOR]

Severe alcohol-associated hepatitis (sAH) is a life-threatening condition with limited treatment options. Corticosteroids are currently recommended as the first-line therapy, but their effectiveness is controversial. Liver transplantation is an option for non-responders, but it is not widely available. A recent study published in the American Journal of Drug and Alcohol Abuse suggests that the use of granulocyte-colony stimulating factor (G-CSF) in combination with pentoxifylline or corticosteroids may be associated with lower mortality rates in sAH. However, conflicting evidence and the need for larger trials indicate that further research is necessary to determine the potential benefits and risks of G-CSF in sAH treatment. In the meantime, supportive therapies, prevention of complications, and alcohol abstinence remain crucial in managing sAH. Public health policies to reduce alcohol use and detect alcohol-related health issues early could also help prevent sAH mortality. [Extracted from the article]

Introduction and Objectives: Liver transplant (LT) is a recent option available in the United States (US) to treat those with severe, refractory alcoholic hepatitis (AH). We examined changes in clinical characteristics of patients admitted with AH and tracked hospital outcomes as practice changes involving LT have shifted. Materials and Methods: Using the National Inpatient Sample, we performed a cross-sectional analysis of patients admitted with AH during the years 2016-2020 in the US. Differences in clinical characteristics over time were assessed. To compare outcomes between 2016-2017 (when LT was less common) and 2018 -2020 (when LT was more common), we conducted linear and logistic regression. Propensity-score matching was used to compare outcomes between patients with and without LT. Results: From 2016-2017 to 2018-2020, patients admitted with AH tended to have a higher frequency of infection (p = 0.006), hepatorenal syndrome (<0.001), and ascites (<0.001). Hospital costs and length of stay (LOS) were highest in transplant hospitals, and costs rose over time in both non-transplant (NT) teaching and non-teaching hospitals (p < 0.001). Mortality decreased in NT teaching hospitals [aOR 0.7 (95% CI: 0.6-0.8)] and slightly decreased in NT non-teaching hospitals [aOR 0.7 (95% CI: 0.5-1.0)]. In the propensity-matched cohort involving LT versus non-LT patients, there was a 10% absolute reduction in-hospital mortality, but this came at a higher cost (p < 0.001) and length of stay (p < 0.001). Conclusions: The severity of AH has been increasing over time, yet mortality has declined after adjusting for severity of disease. Patients who underwent LT survived; however, the healthcare burden of LT is substantial. [ABSTRACT FROM AUTHOR]

A real-world study with clinical and economic assessment of the use of succinate-containing drugs in patients with alcoholic liver disease was conducted. The study was based on data from Buyanov City Clinical Hospital in Moscow and Mirotvortsev Clinical Hospital in Saratov. The period of the study was from 2019 to 2022. The main analyzed factor was the duration of hospitalization and 60 patients with alcoholic liver disease and blood transaminases exceeding two norms and blood ammonia more than one and a half norms were included in the study. Of 60 patients 36 used succinate-containing drugs as part of complex therapy (main group) and 24 did not receive them (control group).The dynamics of indicators of clinical and instrumental status of patients did not differ in both groups (V=0.35; F=0.87; p=0.614). The modelling by Markov chains was performed. The use of succinate-containing drugs demonstrated 8.3 % reducing of costs per case of alcoholic liver disease cure due to the average reduction of hospitalization by 2.42 days.

Clinical manifestations of liver inflammation in alcohol‐associated liver disease (ALD) can range from asymptomatic to severe alcoholic hepatitis. While biopsy is the gold standard for identifying liver inflammation, it is an invasive procedure with risks of bleeding, visceral damage, and infection. We aim to establish the state of the current literature on non‐invasive markers of inflammation in ALD. We searched Ovid MEDLINE, Embase, and the Cochrane Library for original studies on the association between one or more non‐invasive biomarker(s) and histological inflammation or hepatitis in ALD patients. Exclusion criteria were lack of histological data, abstract only, non‐English‐language articles, and animal studies. Two independent reviewers screened abstracts, reviewed full texts, and extracted data from included papers. Our search identified 8051 unique studies. Title and abstract screening resulted in 563 studies, and full‐text screening resulted in 31 studies for final inclusion. The majority were single‐center observational cohorts with an average sample size of 124. Review of these studies identified 44 unique biomarkers and 8 calculated scores associated with histological inflammation and/or hepatitis, in addition to a metabolomic panel of 468 metabolites. Six studies examined diagnostic accuracy for histological inflammation and/or hepatitis. The highest area under the receiver operating characteristic curve was 0.932 using a model based on four metabolites. This review highlights the available literature on non‐invasive markers of inflammation in ALD. There is a dearth of studies that evaluate the diagnostic accuracy of these biomarkers, and larger studies are needed to confirm findings identified in small cohorts. [ABSTRACT FROM AUTHOR]

• Infection is very common in alcoholic hepatitis. • Both infection and alcoholic hepatitis are causes of SIRS. • IL-6 may be able to differentiate when infection is present. Severe alcoholic hepatitis is the most lethal complication in alcohol dependent patients. The concurrence of infections in these patients is very frequent. Both produce a systemic inflammatory response syndrome (SIRS), secondary to intense release of inflammatory cytokines, which can complicate the diagnosis. In our study, Interleukin (IL)-6 and IL-10 levels are higher in patients with SIRS (p <0.001 and p = 0.033, respectively). IL-4, IL-6, Interferon‐gamma (IFNγ), Tumor necrosis factor alpha (TNFα) and IL-17 levels correlate with liver function, as estimated by MELD-Na (p = 0.018, p = 0.008, p = 0.009, p = 0.016 and p = 0.006, respectively). Malondialdehyde (MDA), a product of lipid peroxidation and marker of cell damage, also correlates with liver function (p = 0.002), but not with SIRS or infections. Only elevated IL-6 correlates independently with the presence of infections (RR=1.023 IC 95% 1.000–1.047), so it may be useful for the correct diagnosis in these patients. Values greater than 30 pg/mL have a sensitivity: 86.7% and specificity: 94.7% for the diagnosis of infections. [ABSTRACT FROM AUTHOR]

Background: Severe alcohol-associated hepatitis (SAH) presenting as acute-on-chronic liver failure (ACLF) has high mortality. Severe hepatic inflammation and ongoing hepatocellular cell death lead to rapid rise in portal pressure, a hyperdynamic circulation that might precipitate infections and organ failures. Methods: Consecutive SAH patients were classified based on baseline HVPG measurement as 6to < 12 mmHg, 12to < 20 mmHg, and ≥ 20 mmHg. We analyzed portal hypertension severity in relation to fibrosis stage, ACLF at presentation, response to prednisolone, severity scores(MELD and Maddrey's Discriminant Function, mDF), and 90-day mortality. Results: Of 819 SAH patients (94.6% ACLF, 85.4% histological cirrhosis, median MELD and mDF scores 25 and 66, respectively), 250(30.5%) had HVPG ≥ 20 mmHg. Patients with HVPG ≥ 20 mmHg more often had large esophageal varices (25.2%vs.13.2%; p-0.001), higher baseline MELD (27.1 ± 5.6vs.25.3 ± 5.2; p-0.001), and mDF(76.1 ± 16vs.68.4 ± 15.1; p-0.01) scores. No patient without ACLF had HVPG ≥ 20 mmHg. Moreover, during hospital course these patients had higher incidence of variceal bleed (17.2%vs.8.8%; p-0.001), acute kidney injury (36.4%vs.25.3%; p-0.001), and spontaneous bacterial peritonitis (6.4%vs.3.5%; p-0.05). Of 412(50.3%) eligible patients treated with prednisolone, 69.2% showed response at day 7(Lille's score < 0.45). 90-day mortality was 27.6%; and baseline MELD > 25.5[HR 1.78], HVPG ≥ 20 mmHg [HR 1.86], the presence of HE[HR 1.63], and prednisolone ineligibility due to sepsis[HR 1.27] were independent predictors. Mortality was unrelated to varices grade, variceal bleed, and histological cirrhosis. Repeat HVPG performed in 114(19.2%) patients after a median of 5.2 months showed significant decrease (3.6 mmHg; p-0.001) which correlated with improvement in MELD score(13points; p-0.05). Conclusion: Development of ACLF and complications in SAH are likely a result of acute rise in HVPG. "High-risk" SAH are SAH patients with HVPG ≥ 20 mmHg in the presence of ascites. Understanding the drivers for acute rise in portal pressure in SAH ACLF might help introduction of newer therapies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective To screen key autophagy-related genes in alcoholic hepatitis (AH) and investigate potential biomarkers and therapeutic targets for AH. Methods Two AH gene chips in Gene Expression Omnibus (GEO) and autophagy-related data sets obtained from MSigDB and GeneCards databases were used, and the key genes were verified and obtained by weighted gene co-expression network analysis (WGCNA). The screened key genes were subject to gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein-protein interaction (PPI) and immune infiltration analyses. Messenger RNA (mRNA)- microRNA (miRNA) network was constructed to analyze the expression differences of key autophagy-related genes during different stages of AH, which were further validated by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) in the liver tissues of AH patients and mice. Results Eleven autophagy-related genes were screened in AH (EEF1A2, CFTR, SOX4, TREM2, CTHRC1, HSPB8, TUBB3, PRKAA2, RNASE1, MTCL1 and HGF), all of which were up-regulated. In the liver tissues of AH patients and mice, the relative expression levels of SOX4, TREM2, HSPB8 and PRKAA2 in the AH group were higher than those in the control group. Conclusions SOX4, TREM2, HSPB8 and PRKAA2 may be potential biomarkers and therapeutic targets for AH. [ABSTRACT FROM AUTHOR]

In this research, the influence of hirsutidin on mice with alcoholic liver disease was examined. A total of 30 mice were randomly allocated to five groups (n = 6): Normal control group, Ethanol (EtOH) control group, hirsutidin-10, hirsutidin-20, and hirsutidin-20 per se for 4-week. Further-more, 1 h after the last dosage of the treatment, 5 mL/kg (i.p.) EtOH (56%) was injected to cause hepatic injury. After 5 h of EtOH administration, blood samples were taken, and then the liver was excised for biochemical analysis. Hirsutidin treatment restored the biochemical changes induced by EtOH: serum levels of liver function tests, lipid profile, blood urea nitrogen, antioxidants levels, malondialdehyde, and cytokines. Hirsutidin supplementation also significantly decreased the histopathological abnormalities in EtOH-induced mice. In the present study, hirsutidin was found to have therapeutic potential for the treatment of alcoholic liver disease. Hirsutidin prevented ethanol-induced biochemical and histopathological alterations in the liver, suggesting its hepatoprotective effect. [ABSTRACT FROM AUTHOR]

Objective: Alcoholic hepatitis (AH) is a severe liver disease caused by excessive alcohol consumption. Urban South Indians face unique socio-demographic characteristics and lifestyle choices that may increase their susceptibility to AH. Understanding the prevalence of AH and factors contributing to corticosteroid resistance in this population is essential for effective management and treatment. Methods: A cross-sectional study was conducted among early-stage AH patients in urban South India. Clinical and demographic data, including alcohol consumption patterns, disease severity, and laboratory parameters, were collected. The Lille Score, a validated tool for assessing corticosteroid response, was used to identify patients resistant to treatment. Statistical analyses, including descriptive and inferential statistics, were performed to determine AH prevalence and explore the association between corticosteroid resistance and clinical variables. Results: A total of 540 AH patients were included in the analysis. The non-responder group exhibited varying levels of different parameters throughout the study, with some improving and others remaining relatively stable. The findings provide insights into the progression and features of AH in non-responder patients over time. Conclusion: This study highlights the burden of AH and identifies factors associated with corticosteroid resistance in urban South Indians. The results have implications for clinical practice and public health interventions, emphasizing the need for early detection and targeted treatment strategies. Further research is warranted to enhance our understanding of AH management in diverse populations and regions. [ABSTRACT FROM AUTHOR]

The aggravating role of long noncoding RNA (lncRNA) HOTAIR has been indicated in liver injury caused by hepatic ischemia/reperfusion. However, under the condition of alcoholic hepatitis (AH), its effects remain unclear. The present study aimed to examine the effect of lncRNA HOTAIR on hepatic stellate cell viability and apoptosis during liver injury caused by AH. In the liver tissues of AH rats, HOTAIR and S1PR1 were overexpressed, and microRNA (miR)-148a-3p was poorly expressed. Loss-of-function assays revealed that silencing of HOTAIR alleviated liver injury in AH by inhibiting the activated phenotype of hepatic stellate cells, inflammation, and fibrosis. Using the bioinformatics databases, dual-luciferase, RIP, and FISH assays, we observed that HOTAIR was mainly localized in the cytoplasm of hepatic stellate cells, and HOTAIR could bind specifically to miR-148a-3p. In addition, miR-148a-3p could target S1PR1 expression. Rescue experiments showed that silencing of miR-148a-3p or overexpression of S1PR1 reversed the alleviating effects of HOTAIR silencing on liver injury. Taken together, our findings revealed that HOTAIR regulates hepatic stellate cell proliferation via the miR-148a-3p/S1PR1 axis in liver injury, which may serve as the basis for developing novel therapeutic strategies to treat AH. [ABSTRACT FROM AUTHOR]

Alcohol consumption has been linked to numerous negative health outcomes although it has some beneficial effects on moderate dosages, the most severe of which being alcohol‐induced hepatitis. The number of people dying from this liver illness has been shown to climb steadily over time, and its prevalence has been increasing. Researchers have found that alcohol consumption primarily affects the brain, leading to a wide range of neurological and psychological diseases. High‐alcohol‐consumption addicts not only experienced seizures, but also ataxia, aggression, social anxiety, and variceal hemorrhage that ultimately resulted in death, ascites, and schizophrenia. Drugs treating this liver condition are limited and can cause serious side effects like depression. Serine‐threonine kinases, cAMP protein kinases, protein kinase C, ERK, RACK 1, Homer 2, and more have all been observed to have their signaling pathways disrupted by alcohol, and alcohol has also been linked to epigenetic changes. In addition, alcohol consumption induces dysbiosis by changing the composition of the microbiome found in the gastrointestinal tract. Although more studies are needed, those that have been done suggest that probiotics aid in keeping the various microbiota concentrations stable. It has been argued that reducing one's alcohol intake may seem less harmful because excessive drinking is a lifestyle disorder. [ABSTRACT FROM AUTHOR]

Introduction and Objectives: Liver transplant (LT) is a recent option available in the United States (US) to treat those with severe, refractory alcoholic hepatitis (AH). We examined changes in clinical characteristics of patients admitted with AH and tracked hospital outcomes as practice changes involving LT have shifted. Materials and Methods: Using the National Inpatient Sample, we performed a cross-sectional analysis of patients admitted with AH during the years 2016–2020 in the US. Differences in clinical characteristics over time were assessed. To compare outcomes between 2016–2017 (when LT was less common) and 2018–2020 (when LT was more common), we conducted linear and logistic regression. Propensity-score matching was used to compare outcomes between patients with and without LT. Results: From 2016–2017 to 2018–2020, patients admitted with AH tended to have a higher frequency of infection (p = 0.006), hepatorenal syndrome (

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 crosssectional 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.

BackgroundAlcohol-related hepatitis is one of the most severe manifestations of alcohol-related liver disease and has been associated with significant morbidity, mortality and financial burden. Patients with alcohol use disorders are at risk of leaving against medical advice (LAMA); however, there is currently a lack of data in the literature to show which patients are at higher risk. In this study, we investigated the specific demographic factors and comorbidities associated with LAMA.MethodsPatients with a primary or secondary discharge diagnosis of alcohol-related hepatitis (ICD10-CM codes K70.4 and K70.1) between January 2016 and December 2019 were included in this study. Demographics, comorbidities, complications and interventions were studied in for patients who LAMA. Multivariate analysis was conducted to elucidate factors contributing to the increased risk of alcohol-related hepatitis.ResultsA total of 538,750 patients were admitted with a diagnosis of alcohol-related hepatitis. Of these, 31,500 (5.84%) patients LAMA. Older age, Hispanic race, private insurance, and higher income status were associated with a lower risk of LAMA, while younger age, African American race, lack of insurance and being in the lowest income quartile were associated with the highest risk.ConclusionsOur findings demonstrated that significant differences exist between patients with alcohol-related hepatitis who LAMA and those who remain hospitalized until discharge. We believe that this study will help healthcare providers identify patients at risk of LAMA, and help promote the targeted education of specific subgroups to improve their understanding of their disease state and decrease adverse events.

Purpose: The burden of alcohol-associated liver disease (ALD) in the United States (US) has continued to worsen in the background of rising rates of alcohol use disorder. Patients with ALD present to care at a late stage, often with the sequela of liver decompensation, such as gastrointestinal bleeding and infection. ALD is now the leading indication for liver transplantation. We aimed to measure the quality of care delivered to hospitalized patients with alcoholic hepatitis (AH) across 3 domains: 1) alcohol-use disorder (AUD) care, 2) inpatient cirrhosis care, and 3) alcohol-associated liver disease (ALD) care-and observe associations between quality of care and outcomes.Methods: We included hospital encounters between January 1, 2016 and January 1, 2019 to a large, diverse integrated health system for AH with active alcohol use within the prior 60 days. The diagnosis of AH was determined based on previously published clinical and laboratory criteria. Quality indicator (QI) pass rates were calculated as the proportion of patients eligible for each indicator who received the QI within the timeframe specified. We then evaluated the association between the receipt of all QIs and 6-month mortality, as well as AUD-specific QIs and 30-day readmission.Results: Of the 179 patients, the median age was 47 years-old, 59.2% were male and 49.2% were non-Hispanic White. The median Model for End-Stage Liver Disease-Sodium score was 25, while the median discriminant function was 33. Patients were followed for an average of 21 months. Overall, 14% of patients died during the index hospitalization while 17.3% died following discharge and 24.8% were re-admitted within 30-days. QI pass-rates were variable across the different domains. Few patients received AUD care-pass rates for receipt of pharmacotherapy and behavioral therapy at 6 months were only 19.1% and 35.1%, respectively. There was a significant association between receiving behavioral therapy and 6-month mortality-3% vs 18%, p = 0.05.Conclusion: The quality of care received during hospital encounters for AH is variable, and AUD-specific therapy is low. Future quality of care initiatives are warranted to link patients to AUD treatment to ensure optimal care and maximize patients survival in this at-risk population.

Introduction: Alcoholic hepatitis is a major health problem which carries a high mortality despite treatment. Predicting severity of disease is of utmost importance to avoid overzealous and unnecessary treatment with steroids in each and every case. Maddrey’s discriminant function (DF) may not always be reliable in predicting such prognosis. Aim of the Study: To observe the predictive ability of Glasgow alcoholic hepatitis score (GAHS), age, bilirubin, international normalized ratio (INR) and creatinine (ABIC) score, model for end stage liver disease (MELD) score, and Lille’s score in determining the prognosis in severe alcoholic hepatitis. Materials and Methods: Patients of severe alcoholic hepatitis were enrolled in this study as per inclusion and exclusion criteria and a DF score of >32. Once the decision to initiate corticosteroids was made, DF scores, MELD scores, GAHS scores, and ABIC scores were calculated on the day on initiation of therapy. On day 7, patients were re-assessed and Lille score was calculated in addition. Follow-up was obtained on repeat out-patient visit or telephonically after every 2 weeks till 90 days or till mortality, whichever occurred first. Statistical Analysis: The scores were compared among the survival and mortality groups to see association between mortality and severity of scores using Chi-square test of significance. Cut-offs providing a composite of best sensitivity, specificity, negative predictive value, and positive predictive value were derived on the basis of data of our study. P value of ≤ 0.05 was taken as a cut-off for significance. Results: Our study comprised 30 patients with severe alcoholic hepatitis. At the end of 90-day follow-up, 23 patients survived with 7 (23%) mortalities because of liver failure and sepsis. On day 7, barring the ABIC score (0.713), the areas under curve of all scores were above 0.8 and were hence of comparable efficacy. Lille score performed the best at assessing treatment response but had the limitation of not being applicable at day 1. Conclusion: Severe alcoholic hepatitis carries a bad prognosis. Cut-offs of DF and MELD need to be raised, whereas they need to be lowered in the case of GAHS, ABIC, and Lille score to improve the predictive value of score. Steroid-treated patients should be evaluated preferably with Lille score for a better prediction of survival.

Background: Glucocorticoids (GCs) are widely used in the treatment of inflammatory liver diseases and sepsis, but GC’s various side effects on extrahepatic tissues limit their clinical benefits. Liver-targeting GC therapy may have multiple advantages over systemic GC therapy. The purpose of this study was to develop novel liver-targeting GC prodrugs as improved treatment for inflammatory liver diseases and sepsis. Methods: A hydrophilic linker or an ultra-hydrophilic zwitterionic linker carboxylic betaine (CB) was used to bridge cholic acid (CA) and dexamethasone (DEX) to generate transporter-dependent liver-targeting GC prodrugs CA-DEX and the highly hydrophilic CA-CB-DEX. The efficacy of liver-targeting DEX prodrugs and DEX were determined in primary human hepatocytes (PHH), macrophages, human whole blood, and/or mice with sepsis induced by cecal ligation and puncture. Results: CA-DEX was moderately water soluble, whereas CA-CB-DEX was highly water soluble. CA-CB-DEX and CA-DEX displayed highly transporter-dependent activities in reporter assays. Data mining found marked dysregulation of many GR-target genes important for lipid catabolism, cytoprotection, and inflammation in patients with severe alcoholic hepatitis. These key GR-target genes were similarly and rapidly (within 6 h) induced or down-regulated by CA-CB-DEX and DEX in PHH. CA-CB-DEX had much weaker inhibitory effects than DEX on endotoxin-induced cytokines in mouse macrophages and human whole blood. In contrast, CA-CB-DEX exerted more potent anti-inflammatory effects than DEX in livers of septic mice. Conclusions: CA-CB-DEX demonstrated good hepatocyte-selectivity in vitro and better anti-inflammatory effects in vivo. Further test of CA-CB-DEX as a novel liver-targeting GC prodrug for inflammatory liver diseases and sepsis is warranted.

The pathogenesis of antibodies in severe alcoholic hepatitis (SAH) remains unknown. We analyzed immunoglobulins (Ig) in explanted livers from SAH patients (n=45) undergoing liver transplantation and tissues from corresponding healthy donors (HD, n=10) and found massive deposition of IgG and IgA isotype antibodies associated with complement fragment C3d and C4d staining in ballooned hepatocytes in SAH livers. Ig extracted from SAH livers, but not patient serum exhibited hepatocyte killing efficacy. Employing human and Escherichia coli K12 proteome arrays, we profiled the antibodies extracted from explanted SAH, livers with other diseases, and HD livers. Compared with their counterparts extracted from livers with other diseases and HD, antibodies of IgG and IgA isotypes were highly accumulated in SAH and recognized a unique set of human proteins and E. coli antigens. Further, both Ig- and E. coli-captured Ig from SAH livers recognized common autoantigens enriched in several cellular components including cytosol and cytoplasm (IgG and IgA), nucleus, mitochondrion, and focal adhesion (IgG). Except IgM from primary biliary cholangitis livers, no common autoantigen was recognized by Ig- and E. coli-captured Ig from livers with other diseases. These findings demonstrate the presence of cross-reacting anti-bacterial IgG and IgA autoantibodies in SAH livers.

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Portal venous thrombosis (PVT) is a rare diagnosis in the general population. However, it is seen in patients with liver cirrhosis with an estimated prevalence ranging from 0.6% to 26%. Literature reports that about one-third of PVT cases have an unknown etiology. Identifying the precipitating factors implicated in the development of PVT is imperative as it may help guide therapy. Although the association between liver cirrhosis and PVT has been well established in current literature, there continues to be a relative lack of awareness of alcoholic hepatitis (AH) as a risk factor for PVT. Identifying AH as a trigger for thrombosis can help avoid extended anticoagulation and its complications. In the following case report and brief review, we discuss an uncommon case of a 33-year-old male who came to the hospital emergency department with complaints of nauseousness, abdominal discomfort, and yellow discoloration. Lab investigations showed transaminitis. The diagnosis of AH was established, and an abdominal duplex ultrasound revealed PVT. Heparin drip was started as a part of treatment, which improved his abdominal discomfort. He was eventually discharged on apixaban 5 mg twice daily for 3 months and a repeat abdominal duplex ultrasound in 3 months to check for the resolution of the PVT. [ABSTRACT FROM AUTHOR]

Alcohol-related liver disease is a major cause of liver disease-associated mortality, with inpatient care being a major contributor to its clinical and economic burden. Alcohol-related hepatitis (AH) is an acute inflammatory form of alcohol-related liver disease. Severe AH is associated with high short-term mortality, with infection being a common cause of death. The presence of AH is associated with increased numbers of circulating and hepatic neutrophils. We review the literature on the role of neutrophils in AH. In particular, we explain how neutrophils are recruited to the inflamed liver and how their antimicrobial functions (chemotaxis, phagocytosis, oxidative burst, NETosis) may be altered in AH. We highlight evidence for the existence of 'high-density' and 'low-density' neutrophil subsets. We also describe the potentially beneficial roles of neutrophils in the resolution of injury in AH through their effects on macrophage polarisation and hepatic regeneration. Finally, we discuss how manipulation of neutrophil recruitment/function may be used as a therapeutic strategy in AH. For example, correction of gut dysbiosis in AH could help to prevent excess neutrophil activation, or treatments could aim to enhance miR-223 function in AH. The development of markers that can reliably distinguish neutrophil subsets and of animal models that accurately reproduce human disease will be crucial for facilitating translational research in this important field. [ABSTRACT FROM AUTHOR]