-
Clinics in Liver Disease Aug 2021The incidence of alcoholic hepatitis is increasing while the mortality rate remains high. The single current available therapy for severe alcoholic hepatitis is... (Review)
Review
The incidence of alcoholic hepatitis is increasing while the mortality rate remains high. The single current available therapy for severe alcoholic hepatitis is administration of corticosteroids for patients with severe alcoholic hepatitis, which has demonstrated limited benefits, providing a short-term mortality benefit with a marginal response rate. There is a need for developing safe and effective therapies. This article reviews novel therapies targeting various mechanisms in the pathogenesis of alcoholic hepatitis, such as the gut-liver axis, inflammatory cascade, oxidative stress, and hepatic regeneration. Current ongoing clinical trials for alcoholic hepatitis also are described.
Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents; Hepatitis, Alcoholic; Humans; Liver Transplantation
PubMed: 34229843
DOI: 10.1016/j.cld.2021.03.006 -
F1000Research 2020Alcoholic hepatitis is the severest clinical presentation of alcoholic liver disease. Lacking an effective pharmacologic treatment, alcoholic hepatitis is associated... (Review)
Review
Alcoholic hepatitis is the severest clinical presentation of alcoholic liver disease. Lacking an effective pharmacologic treatment, alcoholic hepatitis is associated with a poor prognosis and its recovery relies mostly on abstinence. With alcohol use disorder being universally on the rise, the impact of alcoholic hepatitis on society and health-care costs is expected to increase significantly. Prognostic factors and liver biopsy can help with timely diagnosis, to determine eligibility and response to corticosteroids, and for prognostication and transplant referral. Although recent discoveries in the pathophysiology of alcoholic hepatitis are encouraging and could pave the way for novel treatment modalities, a multidisciplinary approach considering timely identification and treatment of liver-related complications, infectious and metabolic disease, malnutrition, and addiction counseling should be emphasized. Apart from proper selection of candidates, transplant programs should provide adequate post-transplant addiction support in order to make of early liver transplantation for alcoholic hepatitis the ultimate sobering experience in the next decade.
Topics: Hepatitis, Alcoholic; Humans; Liver Diseases, Alcoholic; Liver Transplantation
PubMed: 32089834
DOI: 10.12688/f1000research.20394.1 -
Liver International : Official Journal... Oct 2023Alcohol-associated liver disease is the primary cause of liver-related mortality worldwide and one of the most common indications for liver transplantation. Alcoholic... (Review)
Review
Alcohol-associated liver disease is the primary cause of liver-related mortality worldwide and one of the most common indications for liver transplantation. Alcoholic hepatitis represents the most acute and severe manifestation of alcohol-associated liver disease and is characterized by a rapid onset of jaundice with progressive inflammatory liver injury, worsening of portal hypertension, and an increased risk for multiorgan failure in patients with excessive alcohol consumption. Severe alcoholic hepatitis is associated with a poor prognosis and high short-term mortality. During the COVID-19 pandemic, rates of alcohol-associated hepatitis have increased significantly, underscoring that it is a serious and growing health problem. However, adequate management of alcohol-associated hepatitis and its complications in everyday clinical practice remains a major challenge. Currently, pharmacotherapy is limited to corticosteroids, although these have only a moderate effect on reducing short-term mortality. In recent years, translational studies deciphering key mechanisms of disease development and progression have led to important advances in the understanding of the pathogenesis of alcoholic hepatitis. Emerging pathophysiology-based therapeutic approaches include anti-inflammatory agents, modifications of the gut-liver axis and intestinal dysbiosis, epigenetic modulation, antioxidants, and drugs targeting liver regeneration. Concurrently, evidence is increasing that early liver transplantation is a safe treatment option with important survival benefits in selected patients with severe alcoholic hepatitis not responding to medical treatment. This narrative review describes current pathophysiology and management concepts of alcoholic hepatitis, provides an update on emerging treatment options, and focuses on the need for holistic and patient-centred treatment approaches to improve prognosis.
Topics: Humans; Hepatitis, Alcoholic; Pandemics; COVID-19; Liver Diseases, Alcoholic
PubMed: 37605624
DOI: 10.1111/liv.15701 -
Journal of Hepatology Aug 2018A 33-year-old Caucasian male was admitted to hospital with recent onset of jaundice of 2-3 weeks duration. He reported heavy use of alcohol for the last 10 years... (Review)
Review
A 33-year-old Caucasian male was admitted to hospital with recent onset of jaundice of 2-3 weeks duration. He reported heavy use of alcohol for the last 10 years with the last drink a day prior to the onset of symptoms. At admission, he was alert and oriented to time, place, and person, and was deeply jaundiced. His laboratory profile can be summarised as follows: haemoglobin 12.1 g/dl, white blood cell count 18,700 with 81% neutrophils, serum bilirubin 33 (direct 22) mg/dl, aspartate aminotransferase 147 IU/L, alanine aminotransferase 62 IU/L, alkaline phosphatase 117 IU/L, serum albumin 2.8 gm/dl, serum creatinine 0.6 mg/dl, prothrombin time 18.3 (control 14.5) seconds, and international normalized ratio 1.48. He was diagnosed with severe alcoholic hepatitis (Maddrey discriminant function score of 50) and treated with prednisolone for 28 days with symptomatic and biochemical improvement. His Lille score at seven days was 0.4, and his serum bilirubin had decreased to 3.5 mg/dl at the end of treatment. He was also seen by the addiction team during hospitalisation; he agreed to follow through on recommendations. He was dismissed after completing a three-week inpatient rehabilitation programme but relapsed to alcohol use three months later, and was readmitted with alcohol withdrawal. He was readmitted two months later (about six months from the first episode) for a second episode of severe alcoholic hepatitis. At admission, his model for end-stage liver disease score was 32 and he was treated again with corticosteroids. His Lille score at seven days was 0.6 and steroids were discontinued. The hospital course was complicated by spontaneous bacterial peritonitis and pneumonia with development of acute kidney injury. He continued to worsen, developing multiorgan failure. After a course of one month, the family's preference was for him to receive comfort measures. This scenario raises several questions.
Topics: Alcoholism; Biopsy; Glucocorticoids; Hepatitis, Alcoholic; Humans; Liver; Liver Transplantation; Prognosis; Severity of Illness Index
PubMed: 29753761
DOI: 10.1016/j.jhep.2018.05.001 -
Gastroenterology Aug 2018We performed a meta-analysis of individual patient data from 11 randomized controlled trials comparing corticosteroids, pentoxifylline, or their combination in patients... (Comparative Study)
Comparative Study Meta-Analysis
Corticosteroids Reduce Risk of Death Within 28 Days for Patients With Severe Alcoholic Hepatitis, Compared With Pentoxifylline or Placebo-a Meta-analysis of Individual Data From Controlled Trials.
BACKGROUND & AIMS
We performed a meta-analysis of individual patient data from 11 randomized controlled trials comparing corticosteroids, pentoxifylline, or their combination in patients with severe alcoholic hepatitis. We compared the effects of the treatments on survival for 28 days or 6 months, and response to treatment based on the Lille model.
METHODS
We searched PubMed for randomized controlled trials of pharmacologic therapy for severe alcoholic hepatitis. Our final analysis comprised 11 studies, of 2111 patients. We performed 4 meta-analyses of the effects of corticosteroids vs placebo or control, corticosteroids vs pentoxifylline, corticosteroids and pentoxifylline vs corticosteroids and placebo or control, and pentoxifylline vs placebo. In each meta-analysis, the effect of treatment on the primary outcome (overall survival at 28 days, defined as the period from the first day of assigned treatment to 28 days) was estimated using a Cox proportional hazards regression model, including trials as random effect.
RESULTS
Corticosteroid treatment significantly decreased risk of death within 28 days compared with controls (hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.48-0.86) or to pentoxifylline (HR 0.64; 95% CI 0.43-0.95). In multiple-imputation and complete case analyses, the effect of corticosteroids compared with controls remained significant. When we compared corticosteroids vs pentoxifylline, the corticosteroid effect remained significant in the complete case analysis (HR 0.66; P = .04) but not in multiple-imputation analysis (HR 0.71; P = .08). There was no difference in 28-day mortality when patients were given a combination of corticosteroids and pentoxifylline vs corticosteroids alone or between patients given pentoxifylline vs control. In our analysis of secondary outcomes, we found no significant differences in 6-month mortality when any treatments or controls were compared. Corticosteroids were significantly associated with increased response to therapy compared with controls (relative risk 1.24; 95% CI 1.10-1.41) or pentoxifylline (relative risk 1.43; 95% CI 1.20-1.68). We found no difference in response to therapy between patients given a combination of corticosteroids and pentoxifylline vs corticosteroids alone or pentoxifylline vs controls.
CONCLUSIONS
In a meta-analysis of 4 controlled trials, we found corticosteroid use to reduce risk of death within 28 days of treatment, but not in the following 6 months. This loss of efficacy over time indicates a need for new therapeutic strategies to improve medium-term outcomes.
Topics: Drug Therapy, Combination; Glucocorticoids; Hepatitis, Alcoholic; Humans; Pentoxifylline; Placebos; Prednisolone; Randomized Controlled Trials as Topic; Severity of Illness Index; Survival Analysis; Time Factors; Treatment Outcome
PubMed: 29738698
DOI: 10.1053/j.gastro.2018.05.011 -
Biomolecules Nov 2015Alcoholic liver disease is one of the most prevalent liver diseases worldwide, and a major cause of morbidity and mortality. Alcoholic hepatitis is a severe form of... (Review)
Review
Alcoholic liver disease is one of the most prevalent liver diseases worldwide, and a major cause of morbidity and mortality. Alcoholic hepatitis is a severe form of liver injury in patients with alcohol abuse, can present as an acute on chronic liver failure associated with a rapid decline in liver synthetic function, and consequent increase in mortality. Despite therapy, about 30%-50% of patients with severe alcoholic hepatitis eventually die. The pathogenic pathways that lead to the development of alcoholic hepatitis are complex and involve oxidative stress, gut dysbiosis, and dysregulation of the innate and adaptive immune system with injury to the parenchymal cells and activation of hepatic stellate cells. As accepted treatment approaches are currently limited, a better understanding of the pathophysiology would be required to generate new approaches that improve outcomes. This review focuses on recent advances in the diagnosis, pathogenesis of alcoholic hepatitis and novel treatment strategies.
Topics: Animals; Hepatitis, Alcoholic; Humans
PubMed: 26540078
DOI: 10.3390/biom5042978 -
Current Opinion in Gastroenterology May 2021The current article aims to review the latest literature on updates in therapeutics for alcohol-associated liver disease (ALD), integration of treatment of alcohol use... (Review)
Review
PURPOSE OF REVIEW
The current article aims to review the latest literature on updates in therapeutics for alcohol-associated liver disease (ALD), integration of treatment of alcohol use disorder (AUD) into the management of ALD, and the role of liver transplantation for alcoholic hepatitis.
RECENT FINDINGS
ALD has recently become the most common indication for liver transplantation due to the increasing prevalence of AUD and the paucity of therapeutic options. There is broad consensus on the importance of early identification of AUD and the incorporation of its treatment in the management of ALD. New targets for treatment of alcoholic hepatitis include the gut-liver axis, anti-inflammatory drugs, antioxidants, and drugs with hepatic regenerative potential. Fecal transplantation in particular has had favorable outcomes at 1 year. n-Acetylcysteine in addition to corticosteroids, granulocyte colony stimulating factor, and IL-22 have also shown improved short-term outcomes. A number of other therapies are being studied in clinical trials and their results are anxiously awaited.
SUMMARY
In summary, there are several promising therapeutic options under clinical investigation for the treatment of alcoholic hepatitis and ALD; however, alcohol abstinence is key. In the absence of other effective therapies, liver transplantation for ALD remains a life-saving treatment with excellent patient and graft survival.
Topics: Alcohol Abstinence; Fecal Microbiota Transplantation; Hepatitis, Alcoholic; Humans; Liver Diseases, Alcoholic; Liver Transplantation
PubMed: 33769374
DOI: 10.1097/MOG.0000000000000725 -
Hepatology International Sep 2020Alcoholic hepatitis (AH) is a clinical syndrome characterized by jaundice and progressive inflammatory liver injury in patients with a history of prolonged periods of... (Review)
Review
Alcoholic hepatitis (AH) is a clinical syndrome characterized by jaundice and progressive inflammatory liver injury in patients with a history of prolonged periods of excess alcohol consumption and recent heavy alcohol abuse. Severe AH is a life-threatening form of alcohol-associated liver disease with a high short-term mortality rate around 30-50% at one month from the initial presentation. A large number of pro-inflammatory mediators, metabolic pathways, transcriptional factors and epigenetic factors have been suggested to be associated with the development and progression of AH. Several factors may contribute to liver failure and mortality in patients with severe AH including hepatocyte death, inflammation, and impaired liver regeneration. Although the pathogeneses of AH have been extensively investigated and many therapeutic targets have been identified over the last five decades, no new drugs for AH have been successfully developed. In this review, we discuss interleukin-22 (IL-22) biology and its roles of anti-apoptosis, anti-fibrosis, anti-oxidation, anti-bacterial infection and regenerative stimulation in protecting against liver injury in many preclinical models including several recently developed models such as chronic-plus-binge ethanol feeding, acute-on-chronic liver failure, C-X-C motif chemokine ligand 1 plus high-fat diet-induced nonalcoholic steatohepatitis. Finally, clinical trials of IL-22 for the treatment of AH are also discussed, which showed some promising benefits for AH patients.
Topics: Hepatitis, Alcoholic; Humans; Interleukins; Liver; Liver Regeneration; Models, Biological; Interleukin-22
PubMed: 32892258
DOI: 10.1007/s12072-020-10082-6 -
Seminars in Liver Disease Feb 2023Alcohol-associated liver disease is a leading cause of mortality and morbidity worldwide. Patients with alcohol-associated liver disease are often diagnosed at advanced... (Review)
Review
Alcohol-associated liver disease is a leading cause of mortality and morbidity worldwide. Patients with alcohol-associated liver disease are often diagnosed at advanced stage and disease spectrum including alcoholic hepatitis, a severe manifestation with a high short-term mortality. Corticosteroid, recommended first-line treatment for patients with alcoholic hepatitis, is a very suboptimal treatment. Although the use of early liver transplantation has increased with consistent benefit in select patients with alcoholic hepatitis, its use remains heterogeneous worldwide due to lack of uniform selection criteria. Over the last decade, several therapeutic targets have evolved of promise with ongoing clinical trials in patients with cirrhosis and alcoholic hepatitis. Even with availability of effective medical therapies for alcohol-associated liver disease, long-term outcome depends on abstinence from alcohol use in any spectrum of alcohol-associated liver disease. However, alcohol use disorder treatment remains underutilized due to several barriers even in patients with advanced disease. There is an urgent unmet need to implement and promote integrated multidisciplinary care model with hepatologists and addiction experts to provide comprehensive management for these patients. In this review, we will discuss newer therapies targeting liver disease and therapies targeting alcohol use disorder in patients with alcohol-associated liver disease.
Topics: Humans; Hepatitis, Alcoholic; Alcoholism; Liver Diseases, Alcoholic; Alcohol Drinking; Treatment Outcome
PubMed: 36572032
DOI: 10.1055/s-0042-1759614 -
Clinics in Liver Disease Aug 2021Alcoholic hepatitis (AH) is a clinical syndrome of jaundice, abdominal pain, and anorexia due to prolonged heavy alcohol intake, and is associated with alterations in... (Review)
Review
Alcoholic hepatitis (AH) is a clinical syndrome of jaundice, abdominal pain, and anorexia due to prolonged heavy alcohol intake, and is associated with alterations in gene expression, cytokines, immune response, and the gut microbiome. Currently, we have limited biomarkers to diagnose and prognosticate in AH, but there are many novel noninvasive biomarkers under development. We evaluate the currently used algorithms to risk-stratify in AH (such as the Maddrey modified discriminant function), and discuss novel biomarkers in development, such as breath biomarkers, microRNAs, cytokeratin-18 fragments, and the AshTest. We also review the characteristics of an ideal biomarker in AH.
Topics: Biomarkers; Gastrointestinal Microbiome; Hepatitis, Alcoholic; Humans; MicroRNAs
PubMed: 34229836
DOI: 10.1016/j.cld.2021.03.010