Treatment Of Alcoholic Hepatitis Research Articles

Severe Alcoholic Hepatitis-optimizing Medical Management: Whether we need a Liver Transplant

Severe alcoholic hepatitis is an ethical and clinical conundrum, wherein a liver transplant is often recommended. The adequacy of medical treatment versus the risk of recidivism after transplant is often debated. Complete recovery in 26 of 27 patients with severe alcoholic hepatitis was observed, and hence the data was retrospectively analysed. Methods: 27 patients, with severe alcoholic hepatitis, with Maddrey's discriminant function between 59.7 to 165.2 (mean 107.53), from June 2017 to May 2022, were followed up for between 11 months to 6 years. INR ranged from 1.99 to 3.7 (mean 2.709), and bilirubin was between 7.6 to 37.01, (mean 20.859). 8 patients had pre-existing liver cirrhosis. All patients received probiotics, nutritional support, physical rehabilitation, saturated fat (clarified butter/ desi ghee) supplementation, and anti-oxidant support. At 90 days, total bilirubin improved to between 1.0 to 6.8 (mean 2.625). ALT (Alanine Transaminase/ SGPT) ranged from 65 to 550 (mean ALT – 197); and AST (Aspartate Transaminase / SGOT) ranged from 58 to 810 (mean AST – 271.51). Both the AST and ALT were near normal after 90 days. One patient died due to bacterial pneumonia and sepsis; the remaining 26 patients made a complete recovery. All patients including those with diagnosed liver cirrhosis, had complete resolution of their ascites, and near-normal liver function. At the last outpatient visit, none had ascites, edema, or encephalopathy, and had normal albumin levels and INR values. Conclusion: Probiotics, nutrition, a saturated fat diet, and exercise; all have shown benefits in patients with severe alcoholic hepatitis when tested individually. Concomitant use of all the above has not been reported in the treatment of alcoholic hepatitis. The role of nutrition alone versus the contribution of nutritional deficiencies and the role of gut-derived endotoxemia need to be studied in detail. How to identify patients who need a transplant, if it is needed at all, remains a challenge.

Depletion of Activated Hepatic Stellate Cells and Capillarized Liver Sinusoidal Endothelial Cells Using a Rationally Designed Protein for Nonalcoholic Steatohepatitis and Alcoholic Hepatitis Treatment.

Nonalcoholic steatohepatitis (NASH) and alcoholic hepatitis (AH) affect a large part of the general population worldwide. Dysregulation of lipid metabolism and alcohol toxicity drive disease progression by the activation of hepatic stellate cells and the capillarization of liver sinusoidal endothelial cells. Collagen deposition, along with sinusoidal remodeling, alters sinusoid structure, resulting in hepatic inflammation, portal hypertension, liver failure, and other complications. Efforts were made to develop treatments for NASH and AH. However, the success of such treatments is limited and unpredictable. We report a strategy for NASH and AH treatment involving the induction of integrin αvβ3-mediated cell apoptosis using a rationally designed protein (ProAgio). Integrin αvβ3 is highly expressed in activated hepatic stellate cells (αHSCs), the angiogenic endothelium, and capillarized liver sinusoidal endothelial cells (caLSECs). ProAgio induces the apoptosis of these disease-driving cells, therefore decreasing collagen fibril, reversing sinusoid remodeling, and reducing immune cell infiltration. The reversal of sinusoid remodeling reduces the expression of leukocyte adhesion molecules on LSECs, thus decreasing leukocyte infiltration/activation in the diseased liver. Our studies present a novel and effective approach for NASH and AH treatment.

Modern Therapeutic Approaches to the Treatment of Alcoholic Hepatitis

Treatment of alcoholic hepatitis is critical to improve survival and prevent progression to cirrhosis and liver failure. Traditional treatments, such as alcohol abstinence and symptomatic drug therapy, remain the cornerstones of treatment. However, in recent years, new drugs have emerged that have shown promise in improving outcomes in patients with alcoholic hepatitis. The purpose of this review is to present the most relevant non-drug, drug-based approaches in the treatment of this group of patients, as well as address the issue of the need for early liver transplantation. The objectives of the work included collecting modern scientific data; discussion of the specifics of each treatment method, possible limitations in the context of use in this group of patients, main advantages for patients with alcoholic hepatitis; analysis of research results that highlight the importance of the drugs used in routine practice depending on the severity of the disease. The results of the work emphasize the continued need to use non-drug methods and, based on the results of using validated scales, prescribe individual drug therapy, as well as the need for further research to optimize results in this group of patients.

Phenformin attenuates the oxidative-nitrosative stress in the liver of rats under long-term ethanol administration

Modulation of the AMP-activated protein kinase (AMPK) pathway activity is considered to be a promi­sing option in the development of approaches to chronic alcoholic hepatitis treatment. Phenformin, which is a biguanide, has been reported to increase AMPK activity. The aim of this work was to estimate the effect of phenformin as AMPK activator on the development of oxidative-nitrosative stress in the liver of rats under conditions of long-term ethanol administration. The experiments were performed on 24 male Wistar rats, divided into 4 groups: control; animals, which received phenformin hydrochloride orally at a dose of 10 mg/kg daily for 63 days; animals with a forced intermittent alcoholization for 5 days by intraperitoneal administration of 16.5% ethanol solution in 5% glucose at the rate of 4 ml/kg b.w. and subsequent transfer to 10% ethanol as the only source of drinking; animals with chronic alcohol hepatitis simulation and phenformin administration. Superoxide dismutase, catalase, NO synthase isoforms activity, superoxide anion radical production, concentration of malonic dialdehyde, peroxynitrite, nitrites, nitrosothiols concentration and oxidative modification of proteins (OMP) were estimated in liver homogenates. The increased production of oxygen and nitrogen active forms and OMP intensification in the liver of rats under long-term administration of ethanol was detected. Phenformin introduction under long-term ethanol administration was shown to limit the excess peroxynitrite formation and to prevent oxidative damage to rat liver proteins. Keywords: AMP-activated protein kinase., chronic alcoholic hepatitis, liver, oxidative and nitrosative stress, phenformin

Identifying competing endogenous RNA regulatory networks and hub genes in alcoholic liver disease for early diagnosis and potential therapeutic target insights.

Alcoholic liver disease (ALD) has a complex pathogenesis. Although early-stage ALD can be reversed by ceasing alcohol consumption, early symptoms are difficult to detect, and several factors contribute to making alcohol difficult to quit. Continued alcohol abuse worsens the condition, meaning it may gradually progress into alcoholic hepatitis and cirrhosis, ultimately, resulting in irreversible consequences. Therefore, effective treatments are urgently needed for early-stage ALD. Current research mainly focuses on preventing the progression of alcoholic fatty liver to alcoholic hepatitis and cirrhosis. However, challenges remain in identifying key therapeutic targets and understanding the molecular mechanisms that underlie the treatment of alcoholic hepatitis and cirrhosis, such as the limited discovery of effective therapeutic targets and treatments. Here, we downloaded ALD microarray data from Gene Expression Omnibus and used bioinformatics to compare and identify the hub genes involved in the progression of alcoholic fatty liver to alcoholic hepatitis and cirrhosis. We also predicted target miRNAs and long non-coding RNAs (lncRNAs) to elucidate the regulatory mechanisms (the mRNA-miRNA-lncRNA axis) underlying this progression, thereby building a competitive endogenous RNA (ceRNA) mechanism for lncRNA, miRNA, and mRNA. This study provides a theoretical basis for the early treatment of alcoholic hepatitis and cirrhosis and identifies potential therapeutic targets.

Alcoholic Hepatitis

Alcoholic hepatitis is a serious liver condition characterized by inflammation and liver damage caused by excessive alcohol consumption. This condition represents a significant health concern worldwide as it can progress to more severe liver diseases, including cirrhosis and liver failure. This abstract provides an overview of alcoholic hepatitis, including its causes, symptoms, diagnosis, and treatment. Long-term alcohol consumption is the primary cause of alcoholic hepatitis. When alcohol is metabolized in the liver, it generates toxic byproducts that can lead to inflammation and cellular damage. Over time, repeated episodes of damage can result in alcoholic hepatitis. Patients with this condition may present with various symptoms including jaundice, abdominal pain, nausea, vomiting, fever, and an enlarged liver. Diagnosis of alcoholic hepatitis typically involves a combination of medical history assessment, physical examination, blood tests, and imaging studies. Elevated levels of liver enzymes, such as AST and ALT, are common laboratory findings. A liver biopsy may be required to confirm the diagnosis and assess the extent of liver damage. Treatment of alcoholic hepatitis primarily focuses on alcohol cessation, which is essential to prevent further liver damage and improve the chances of recovery. Supportive care, such as nutritional supplementation and the management of complications, is also essential. Hospitalization may be necessary for severe cases. The prognosis varies depending on the severity of the condition and the patient's response to treatment. Complete abstinence from alcohol significantly improves the chances of recovery; however, some individuals may progress to advanced liver disease or even liver failure. Liver transplantation may be considered for those with end-stage liver disease. key words Alcoholic hepatitis Liver inflammation Excessive alcohol consumption Liver damage Cirrhosis Liver failure Symptoms Jaundice Abdominal pain Nausea Vomiting Fever Enlarged liver Diagnosis Liver enzymes AST (Aspartate Aminotransferase) ALT (Alanine Aminotransferase) Liver biopsy Treatment Alcohol cessation.

Intestinal Microbiotas and Alcoholic Hepatitis: Pathogenesis and Therapeutic Value.

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.

QBD APPROACH FOR THE DEVELOPMENT OF CAPSAICIN-LOADED STEARIC ACID-GRAFTED CHITOSAN POLYMERIC MICELLES

Objective: Capsaicin (CAP) is a naturally occurring alkaloid forecasted in the treatment of Alcoholic Hepatitis (AH), but least studied due to its hydrophobicity and low bioavailability. Hence, the present study aimed to optimize the parameters for the synthesis of stearic acid grafted chitosan (CS-g-SA) copolymer and preparation of CAP-loaded CS-g-SA micelles. Methods: Quality by design (QbD) approach in coordination with “Central composite designs (CCD) and Box–Behnken designs (BBD)” was used to optimize the process parameters. Results: CS-g-SA was synthesized at 80 °C, 480 min, and 946 rpm, at these optimized conditions, the average particle size and practical yield were found to be 134.70 nm and 85.69%, respectively. Proton Nuclear Magnetic Resonance (1H NMR) spectra depicted a sharp signal at d=1.0 ppm endorsing to -CH2 group of SA and confirming the formation of CS-g-SA copolymer. Critical micellar concentration (CMC) and amino groups substitute degree (SD %) were found to be 30.3±1.51µg/ml and 21.3±0.58%, respectively. The distinguished peaks of CAP (0.9 and 1.31 ppm) in 1H NMR spectra disappeared, indicating drug loading in the micellar core. Micelles had an average particle size of 163.15 nm and an encapsulation efficiency of 68.45%. The CAP-CS-g-SA was found to be biocompatible in accordance with the hemolysis test. The in vitro release pattern showed 86.78 % in 24 h, indicating the slower release of CAP from micelle, whereas 99.48% CAP was released from non-micellar formulations in 6 h. Conclusion: CAP-CS-g-SA micelle is a promising approach to improve the bioavailability and controlled release of extremely hydrophobic CAP and further in vivo studies would be evident for the treatment of AH using CAP-CS-g-SA.

QBD APPROACH FOR THE DEVELOPMENT OF CAPSAICIN-LOADED GLYCYRRHETINIC ACID CONJUGATED STEARIC ACID GRAFTED CHITOSAN POLYMERIC MICELLES FOR ACTIVE HEPATIC TARGETING

Objective: Capsaicin (CAP) is a naturally occurring alkaloid forecasted in the treatment of Alcoholic Hepatitis (AH), but least studied due to its hydrophobicity, low bioavailability, and less target-specific release. Hence, the present study aimed to synthesize glycyrrhetinic acid conjugated stearic acid grafted chitosan (GA-CS-g-SA) and prepare CAP-loaded GA-CS-g-SA micelles. Methods: Quality by design (QbD) approach in coordination with "Box-Behnken Designs (BBD)" was used to optimize the process parameters. GA-CS-g-SA was synthesized and characterized for its physic-chemical. Results: The "Proton Nuclear Magnetic Resonance (1H NMR)" spectrum depicted a strong signal at d=1.0 ppm and endorsed to-CH2 group of SA and d=3.5-3.65 ppm depicting GA, which confirms the formation of GA-CS-g-SA. Critical micellar concentration (CMC) was found to be 13.45±1.72 µg/ml and amino groups substitute degree (SD %) was 10.12%±1.09%, indicating successful linkage of GA and SA on CS. The prominent peaks of CAP (0.9 and 1.31 ppm) in 1H NMR spectra disappeared, indicating drug loading in the micellar core. Micelle's normal particle range was 167.54 nm, and encapsulation efficiency was 67.85%. The CAP-GA-CS-g-SA was found to be biocompatible following the hemolysis test. In vitro release pattern showed 78.68±3.12% in 24h, indicating the slower release of CAP from micelle, whereas 99.48±2.56% was released from non-micellar formulations in 6 h. CAP release from drug-loaded micelles showed a biphasic model with an early burst release in four hours, following a slower and sustained release pattern till 24h. Conclusion: CAP-GA-CS-g-SA micelle is a hopeful advancement to progress bioavailability and controlled release of highly hydrophobic CAP. Further in vivo studies would be evident for targeting hepatocytes and treating AH using CAP-GA-CS-g-SA.

PARANOID ABOUT RASHES: OLANZAPINE INDUCED DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS

<h3>Introduction</h3> Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is a severe adverse reaction caused by more than 50 prescription drugs. Although antiepileptics and antibiotics account for most cases, the variety of potential drug classes can make identifying the causative agent challenging. <h3>Case Description</h3> Thirty-year-old male was initially admitted to the medical ICU for treatment of alcoholic hepatitis. Hospital course was complicated by an upper GI bleed, hepatic encephalopathy, respiratory failure, and multiple infections requiring repeated courses of antibiotics. Two months into the hospital stay, he developed a diffuse pruritic maculopapular rash that progressed to cover his trunk, neck and extremities. Workup revealed elevated aminotransferases along with worsening creatinine, leukocytosis, and eosinophilia concerning for DRESS. Medication review revealed the patient received several days of vancomycin in addition to a month-long course of olanzapine for paranoia suffered while inpatient. Patient first received olanzapine 8 weeks prior to symptom onset. HLA-A*32:01 was obtained and negative. Topical steroids were applied, and potential offending medications held. Rash resolved over the next few weeks followed by clinical improvement. Olanzapine was added to the allergy list to avoid future episodes. <h3>Discussion</h3> The diagnosis of DRESS can be challenging as it often occurs in the inpatient setting with patients exposed to varying amounts of multiple drugs, including less common agents such as olanzapine. When multiple culprit drugs have been administered, evaluating factors such as timeline of exposure and genetic predisposition may be helpful in identifying the cause. This can lead to prompt removal of the offending drug minimizing morbidity and mortality.

Liver regeneration as treatment target for severe alcoholic hepatitis.

Severe alcoholic hepatitis (AH) is a distinct entity in the spectrum of alcohol-related liver disease, with limited treatment options and high mortality. Supportive medical care with corticosteroids in selected patients is the only currently available treatment option, often with poor outcomes. Based on the insights into the pathogenetic mechanisms of AH, which are mostly obtained from animal studies, several new treatment options are being explored. Studies have implicated impaired and deranged liver regeneration processes as one of the culprit mechanisms and a potential therapeutic target. Acknowledging evidence for the beneficial effects of granulocyte colony-stimulating factor (G-CSF) on liver regeneration and immunomodulation in animal models, several human studies investigated its role in the treatment of advanced alcohol-related liver disease and AH. Contrary to the previously published studies suggesting benefits of G-CSF in the outcomes of patients with severe AH, these effects were not confirmed by a recently published multicenter randomized trial, suggesting that other options should rather be pursued. Stem cell transplantation represents another option for improving liver regeneration, but evidence for its efficacy in patients with severe AH and advanced alcohol-related liver disease is still very scarce and unconvincing, with established lack of efficacy in patients with compensated cirrhosis. In this review, we summarize the current knowledge on the pathogenesis and experimental therapies targeting liver regeneration. The lack of high-quality studies and evidence is a major obstacle in further treatment development. New insights into the pathogenesis of not only liver injury, but also liver regeneration processes are mandatory for the development of new treatment options. A reliable experimental model of the pathogenesis of AH and processes involved in liver recovery is still missing, and data obtained from animal studies are essential for future research.

Progress in the clinical treatment of alcoholic hepatitis

Alcoholic hepatitis is a severe and life-threatening systemic inflammatory response syndrome, which has a high incidence and mortality rate worldwide. The severity ranges from asymptomatic liver biochemical disturbances to fulminant liver failure or death; however, there are few effective therapeutic interventions. Maddrey discriminant function not only predicts short-term mortality, but it also guides clinicians to choose appropriate alcoholic hepatitis-specific treatments. Alcohol abstinence, nutritional support, psychological counseling, and infection prevention remain the cornerstones for alcoholic hepatitis treatment. Corticosteroids remain the mainstay of treatment when patients have a good appetite and normal serum creatinine levels, but early liver transplantation is the only life-saving option for steroid-unresponsive patients. New studies have found that gut microbiota is an important therapeutic targets in patients with alcohol hepatitis, and N-acetylcysteine, granulocyte colony-stimulating factor, and metadoxine as adjunctive therapy have a positive effect on patient survival.

The Integrated Analysis of Transcriptomics and Metabolomics Unveils the Therapeutical Effect of Asiatic Acid on Alcoholic Hepatitis in Rats.

The present study was to investigate the therapeutical effects and mechanisms of Asiatic acid from Potentilla chinensis against alcoholic hepatitis. Rats were intragastrically fed with alcohol for 12weeks to induce alcoholic hepatitis and then treated with various drugs for further 12weeks. The results showed that Asiatic acid significantly alleviated liver injury caused by alcohol in rats, as evidenced by the improved histological changes and the lower levels of AST, ALT, and TBIL. Besides, Asiatic acid significantly enhanced the activity of ADH and ALDH, promoting alcohol metabolism. Asiatic acid suppressed CYP2E1 activity and NADP+/NADPH ratio, resulting in low ROS production. Further study revealed that Asiatic acid markedly reduced hepatocyte apoptosis by regulating the expression levels of apoptosis-related protein. Moreover, Asiatic acid could regulate the Nrf2 and NF-κB signaling pathway, attenuating oxidative stress and inflammation as a result. Interestingly, the comprehensive analysis of transcriptomics and metabolomics indicated that Asiatic acid inhibited the gene expression of Gpat3 and thereby affected the biosynthesis of the metabolites (1-acyl-Sn-glycerol-3-phosphocholine, phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine), regulating the glycerophospholipid metabolism pathway and ultimately ameliorating hepatocyte damage. In conclusion, this study demonstrates that Asiatic acid can ameliorate alcoholic hepatitis by modulating the NF-κB and Nrf2 signaling pathways and the glycerophospholipid metabolism pathway, which may be developed as a potential medicine for the treatment of alcoholic hepatitis.

Rising Trend in Waitlisting for Alcoholic Hepatitis With More Favorable Outcomes Than Other High Model for End-stage Liver Disease in the Current Era.

In the appropriate candidate, liver transplantation (LT) is a viable treatment for alcoholic hepatitis (AH). We compared the waitlisting trends and outcomes of AH patients in the context of others with high Model for End-stage Liver Disease (MELD) score. LT listings for AH between January 1, 2008, and June 12, 2020 were identified in the United Network for Organ Sharing database. Temporal trends in listings for AH were assessed. Covariate adjusted competing risks models evaluated waitlist mortality and LT rates between AH candidates and others with listing native MELD ≥30. Between 2008 and 2019, waitlist additions for AH increased 6.5-fold. Waiting time for AH candidates was short (median 10 d). Delisting for clinical improvement was infrequent in AH, albeit higher than MELD ≥30 patients (3.3% versus 0.8%; P < 0.001). Among 99 centers with ≥1 AH listing, AH patients accounted for 0.2%-18.2% of all alcohol-related listings and 0.6%-25.0% of those with native listing MELD ≥30. Overall listing volume was larger at these 99 centers than the 40 with no AH listings (P < 0.001). AH candidates in 2014-2020 experienced improved waitlist survival (adjusted subhazard ratio, 0.67; 95% confidence interval, 0.52-0.86; P = 0.002) and higher transplant rates (adjusted subhazard ratio, 1.14; 95% confidence interval, 1.04-1.25; P = 0.006) versus other MELD ≥30 candidates. There has been a rising trend in waitlisting patients with AH and high MELD score. Liver disease causes influence waitlist outcomes and those of AH candidates are more favorable. Further research and allocation adjustments may be needed to ensure equitable organ allocation, based on liver disease cause, for those on the LT waitlist.

Intestinal Microbiota Contributes to the Improvement of Alcoholic Hepatitis in Mice Treated With Schisandra chinensis Extract.

Alcoholic hepatitis (AH) has a high short-term mortality rate. Schisandra chinensis has the potential to ameliorate liver damage and be a source of prebiotics. We aimed to investigate whether Schisandra chinensis extract (SCE) can improve AH and the role of the small intestinal and cecal microbiota and their metabolites. UHPLC-QE-MS was used to analyze the chemical components of SCE. The chronic-plus-binge ethanol feeding model was used to induce AH in mice. 1H NMR was used to analyze intestinal metabolites. 16S rRNA-based high throughput sequencing was used to evaluate the effects of SCE on intestinal microbiota (IM). Intestinal microbiota transplantation was used to explore the role of IM in SCE treatment of AH. SCE ameliorated AH non-dose-dependently. SCE effectively improved liver inflammation and oxidative/nitrosative stress, strengthened intestinal barrier function, and regulated the composition of IM and the content of short-chain fatty acids (SCFAs) in AH mice. Samples from in vivo and in vitro SCE-altered IM improved liver status and regulated the IM. The administration of Lactobacillus plantarum and Bifidobacterium breve ameliorated AH to some extent. The administration of Enterococcus faecalis and Klebsiella oxytoca had partial beneficial effects on AH. Collectively, IM and metabolites were closely associated with the improvement of SCE on AH. The possible microbe targets were the growth inhibition of Escherichia-Shigella and the expansion of SCFA producers, such as Lactobacillus and Bifidobacterium. Schisandra chinensis can be considered as a safe and effective dietary supplement for the prevention and improvement of AH.

Health-related quality of life is dynamic in alcoholic hepatitis and responds to improvement in liver disease and reduced alcohol consumption.

The impact of alcoholic hepatitis (AH) on health-related quality of life (HRQOL) remains inadequately described. We aimed to characterize HRQOL in AH and heavy drinkers (HD), and its associations with clinical variables and outcomes. This is a post hoc analysis of participants in the Translational Research and Evolving Alcoholic Hepatitis Treatment 001 study (NCT02172898). HRQOL was measured using Short Form Health Survey (SF-36). Mean SF-36 scores were compared in AH and HD with two-sample t-tests. Associations among clinical characteristics, 30-day mortality, and SF-36 mental and physical component scores (MC, PC) were investigated with generalized linear and logistic multivariate regression models. Trends of MC and PC scores were analyzed using one-way ANOVA. Participants with AH (n=258) and HD (n=181) were similar demographically. AH cases had a mean Model for End-stage Liver Disease (MELD) score of 23 (7). AH cases had lower PC scores [37 (10) vs. 48 (11), p<0.001] but higher MC scores [37 (13) vs. 32 (13), p<0.001]. MC scores were independently associated with age, male gender, and daily alcohol consumption; PC scores were independently associated with age, BMI, alanine aminotransferase concentration, alkaline phosphatase concentration, white blood cell counts, and the presence of ascites. With each 5-point decrease in the baseline PC score, the adjusted odds of dying within 30days increased by 26.7% (95% CI 1% to 46%). Over time, HRQOL in AH improved (day 0 to day 180 delta PC score: 4.5±1.7, p=0.008; delta MC score: 9.8±2.0, p<0.001). Participants with a MELD score <15 by day 180 had greater increases in PC scores than those with MELD score ≥15 (delta PC score 7.1±1.8 vs. -0.7±2.3, p=0.009), while those abstinent by day 180 had greater increases in MC scores than those who were not abstinent (delta MC score 9.1±1.8 vs. 2.8±2.4, p=0.044). HRQOL is poor in AH and HD in a domain-specific pattern. Independent of MELD score, lower baseline HRQOL is associated with higher 30-day mortality. Over time, HRQOL improves with greater gains seen in individuals with improved MELD scores and those who were abstinent.

IL-1 Signal Inhibition In Alcoholic Hepatitis (ISAIAH): a study protocol for a multicentre, randomised, placebo-controlled trial to explore the potential benefits of canakinumab in the treatment of alcoholic hepatitis

BackgroundAlcohol consumption causes a spectrum of liver abnormalities and leads to over 3 million deaths per year. Alcoholic hepatitis (AH) is a florid presentation of alcoholic liver disease characterized by liver failure in the context of recent and heavy alcohol consumption. The aim of this study is to explore the potential benefits of the IL-1β antibody, canakinumab, in the treatment of AH.MethodsThis is a multicentre, double-blind, randomised placebo-controlled trial. Participants will be diagnosed with AH using clinical criteria. Liver biopsy will then confirm that all histological features of AH are present. Up to 58 participants will be recruited into two groups from 15 centres in the UK. Patients will receive an infusion of Canakinumab or matched placebo by random 1:1 allocation. The primary outcome is the difference between groups in the proportion of patients demonstrating histological improvement and will compare histological appearances at baseline with appearances at 28 days to assign a category of “improved” or “not improved”. Patients with evidence of ongoing disease activity will receive a second infusion of canakinumab or placebo. Participants will be followed up for 90 days. Secondary outcomes include mortality and change in MELD score at 90 days.DiscussionThis phase II study will explore the benefits of the IL-1β antibody, canakinumab, in the treatment of AH to provide proof of concept that inhibition of IL-1β signalling may improve histology and survival for patients with AH.Trial registrationEudraCT 2017-003724-79. Prospectively registered on 13 April 2018.

S2776 A Rare Case of Pseudomonas Aeruginosa Colitis and Subsequent Bacteremia in the Setting of Alcohol-Induced Cirrhosis

Introduction: Pseudomonas aeruginosa is an opportunistic bacterium that commonly causes pneumonia and urinary tract infections. While cases of P. aeruginosa colitis have been infrequently reported, we identify a unique case of P. aeruginosa bacteremia occurring after antibiotic-treated P. aeruginosa colitis in a patient with alcohol-induced cirrhosis. Case Description/Methods: A 38-year-old male with class III obesity and alcohol use disorder presented with cramping abdominal pain, vomiting and dark stool. There was no recent hospitalization and no antibiotic or intravenous drug use. Last alcoholic drink was reported to be several days prior to presentation. Physical exam identified scleral icterus, abdominal distension without tenderness, and hepatomegaly. Laboratory test results are outlined in Table 1. Serum acetaminophen and alcohol levels were not detected. Urinalysis and chest x-ray were unremarkable. Ultrasound demonstrated cirrhotic liver morphology and ascites, but no cholelithiasis. Ceftriaxone was started due to concerns for an upper gastrointestinal bleed. On day 2, he developed watery diarrhea. Stool cultures were positive for P. aeruginosa, prompting antibiotic transition to cefepime. Clostridioides difficile testing was negative. He completed a five-day course of cefepime with resolution of diarrhea and leukocytosis. Subsequently, he was started on methylprednisolone for treatment of alcoholic hepatitis, and later discharged on a tapering dose. Eleven days later, he returned with vomiting and generalized weakness, and was admitted to the intensive care unit with pansusceptible P. aeruginosa bacteremia and septic shock. Unfortunately, clinical condition continued to deteriorate despite maximal medical therapy, and he ultimately expired. Discussion: P. aeruginosa has rarely been described in association with colitis. To our knowledge, this is the first reported case of P. aeruginosa colitis in a patient with alcohol-induced cirrhosis, and the first case of P. aeruginosa bacteremia after previously treated colitis. While the optimal duration of treatment for P. aeruginosa colitis is not well defined, this case supports extended antibiotic courses for the treatment of P. aeruginosa infections in decompensated cirrhosis and cautious post-treatment steroid utilization.Table 1.: This table depicts initial admission laboratory testing results for the patient’s two separate admissions.

Super enhancer regulation of cytokine-induced chemokine production in alcoholic hepatitis

Alcoholic hepatitis (AH) is associated with liver neutrophil infiltration through activated cytokine pathways leading to elevated chemokine expression. Super-enhancers are expansive regulatory elements driving augmented gene expression. Here, we explore the mechanistic role of super-enhancers linking cytokine TNFα with chemokine amplification in AH. RNA-seq and histone modification ChIP-seq of human liver explants show upregulation of multiple CXCL chemokines in AH. Liver sinusoidal endothelial cells (LSEC) are identified as an important source of CXCL expression in human liver, regulated by TNFα/NF-κB signaling. A super-enhancer is identified for multiple CXCL genes by multiple approaches. dCas9-KRAB-mediated epigenome editing or pharmacologic inhibition of Bromodomain and Extraterminal (BET) proteins, transcriptional regulators vital to super-enhancer function, decreases chemokine expression in vitro and decreases neutrophil infiltration in murine models of AH. Our findings highlight the role of super-enhancer in propagating inflammatory signaling by inducing chemokine expression and the therapeutic potential of BET inhibition in AH treatment.

Alcoholic Hepatitis – A Fatal Disease

Liver is the vital organ that metabolizes and excretes nutrients. Failure of the liver leads to death in cases. The complication which causes liver failure is excessive alcohol consumption. Liver metabolizes ethanol and it faces the highest degree of injury by uncontrolled drinking. Alcohol use produces a broad spectrum of diseases; hepatosteatosis, Alcoholic hepatitis, fibrosis &amp; cirrhosis. Pathogenesis of Alcohol related Liver Diseases (ALD) is explained by hepatic lipogenesis, deceleration of hepatic lipid breakdown, defective hepatic lipid export, macrophage induced alcoholic hepatitis (AH), Lipopolysaccharide (LPS) transport into the hepatic bloodstream, Malondialdehyde and acetaldehyde (MAA) adducts formation and hepatocyte stellate cell (HSC) induction. Main symptoms of AH include oxidative stress, metabolism interruption, inflammation, restoration process changes and bacterial byproducts misplacement from the gut into hepatic portal blood circulation. Diagnostic studies of ALD are concluded by medical records, clinical and laboratory declarations. Earlier, Glucocorticoids, Pentoxifylline, TNFα were used in the treatment of AH, alone or combined. Novel treatments include Metadoxine, Caspase inhibitors, Microbiome Modification, Microbial Phage Therapy, and liver transplantation. These treatments are prescribed in combination with addiction psychiatrists, social work, and family counselors. Recent studies confirmed that AH could be prevented by consuming capsaicin daily, which ultimately reduces the global burden.