Therapy For Alcoholic Hepatitis Research Articles

Comparison of 1-Year Morbidity Following Liver Transplant for Acute Alcoholic Hepatitis Versus Alcoholic Cirrhosis.

With limited data on the morbidity profile of liver transplant as therapy for alcoholic hepatitis, we compared 30-day and 1-year morbidity in liver transplant recipients with alcoholic hepatitis versus alcoholic cirrhosis. We retrospectively reviewed 38 perioperative variables in patients with alcoholic hepatitis (n = 15) and with alcoholic cirrhosis (n = 46). Multivariable analysis was performed to identify factors independently associated with outcomes. Patients with alcoholic hepatitis were younger (43 vs 58 years; P = .001), with higher pretransplant Model for End-Stage Liver Disease scores (36 vs 29; P = .009) and worse Karnofsky scores (20 vs 50; P < .001). All patients with alcoholic hepatitis received standard criteria deceased donor grafts; however, in the alcoholic cirrhosis group, 64% received standard criteria deceased, 11% living, 11% after cardiac death, 9% extended criteria, and 2% split graft donor organ donations (P > .05). The alcoholic hepatitis group had higher degree of steatosis on explant (P < .005), and the alcoholic cirrhosis group had higher 30-day reoperation rate (P = .001); however, 1-year interventions, vascular and biliary complications, graft and patient survival, and all other variables were similar (P > .05). Rates of alcohol relapse, 1-year infection, and 1-year rejection were higher but not significant (P > .05) in the alcoholic hepatitis group. Thirty-day reoperation (odds ratio of 82.63; 95% CI, 8.02-3338.96; P = .002) and Karnofsky scores (odds ratio of 1.18; 95% CI, 1.08-1.36; P = .006) remained significant on multivariate analysis. Our results showed significant differences between our patient groups, including worse functional status in the alcoholic hepatitis group but significantly higher 30-day reoperation rates and more variable grafts in the alcoholic cirrhosis group, although both groups had similar overall 1-year complication and survival rates. Although not significant, patients with alcoholic hepatitis had higher alcohol relapse and 1-year infection and rejection rates. A larger cohort is necessary to confirm the strength of these findings.

β-Hydroxybutyrate protects from alcohol-induced liver injury via a Hcar2-cAMP dependent pathway

Sterile inflammation resulting in alcoholic hepatitis (AH) occurs unpredictably after many years of excess alcohol intake. The factors responsible for the development of AH are not known but mitochondrial damage with loss of mitochondrial function are common features. Hcar2 is a G-protein coupled receptor which is activated by β-hydroxybutyrate (BHB). We aimed to determine the relevance of the BHB-Hcar2 pathway in alcoholic liver disease. We tested if loss of BHB production can result in increased liver inflammation. We further tested if BHB supplementation is protective in AH through interaction with Hcar2, and analyzed the immune and cellular basis for protection. Humans with AH have reduced hepatic BHB, and inhibition of BHB production in mice aggravated ethanol-induced AH, with higher plasma alanine aminotransferase levels, increased steatosis and greater neutrophil influx. Conversely supplementation of BHB had the opposite effects with reduced alanine aminotransferase levels, reduced steatosis and neutrophil influx. This therapeutic effect of BHB is dependent on the receptor Hcar2. BHB treatment increased liver Il10 transcripts, and promoted the M2 phenotype of intrahepatic macrophages. BHB also increased the transcriptional level of M2 related genes in vitro bone marrow derived macrophages. This skewing towards M2 related genes is dependent on lower mitochondrial membrane potential (Δψ) induced by BHB. Collectively, our data shows that BHB production during excess alcohol consumption has an anti-inflammatory and hepatoprotective role through an Hcar2 dependent pathway. This introduces the concept of metabolite-based therapy for AH. Alcoholic hepatitis is a life-threatening condition with no approved therapy that occurs unexpectedly in people who consume excess alcohol. The liver makes many metabolites, and we demonstrate that loss of one such metabolite β-hydroxybutyrate occurs in patients with alcoholic hepatitis. This loss can increase alcohol-induced liver injury, and β-hydroxybutyrate can protect from alcohol-induced liver injury via a receptor on liver macrophages. This opens the possibility of metabolite-based therapy for alcoholic hepatitis.

Redefining Successful Treatment of Severe Alcoholic Hepatitis.

Redefining Successful Treatment of Severe Alcoholic Hepatitis.

Alcoholic Hepatitis: Risk Factors, Pathogenesis, and Approach to Treatment.

Alcoholic hepatitis (AH) is an inflammatory disorder of the liver characterized clinically by jaundice, hepatomegaly, and abdominal pain, and histologically by macrovesicular steatosis and necroinflammation. This clinical review will cover what is known about the pathogenesis, clinical presentation, current treatments, and novel therapies for AH. The pathogenesis and treatment of AH remain areas of active research. Although abstinence is the cornerstone of therapy for all stages of alcoholic liver disease, corticosteroids have shown modest short-term benefits in treatment of severe AH. Improved understanding of the pathogenesis of AH has expanded the range of potential treatments for this devastating disease. Several novel therapies are also currently in various stages of testing through clinical trials.

Diagnostic and therapeutic strategies for severe alcoholic hepatitis

Alcoholic hepatitis (AH) is defined as an acute hepatic manifestation resulting from heavy alcohol intake. Histologically, alcoholic steatohepatitis (ASH) is characterized by hepatocellular steatosis, inflammation, and fibrosis. Alcohol abstinence is the sine qua non of therapy for AH and, in the milder forms, is prerequisite to clinical recovery. Severe ASH may lead to multi-organ failure such as acute kidney injury and infection, which has a major impact on survival and thus should be closely monitored. Patients with severe ASH have a drastic short-term mortality of up to 40-50%. Specific therapies should be considered for patients with severe ASH at risk of early death. Corticosteroids are the standard of care for patients with severe ASH. When corticosteroids are contraindicated, pentoxifylline may be an alternative option. Steroid responsiveness should be evaluated on the basis of Lille score. Tactically, we should explore novel therapeutic targets to suppress inflammation based on cytokine profiles, promote hepatic regeneration, limit innate immune responses, and restore altered gut mucosal integrity in severe ASH.

Severe alcoholic hepatitis-current concepts, diagnosis and treatment options.

Alcoholic hepatitis (AH) is an acute hepatic manifestation occurring from heavy alcohol ingestion. Alcoholic steatohepatitis (ASH) is histologically characterized by steatosis, inflammation, and fibrosis in the liver. Despite the wide range of severity at presentation, those with severe ASH (Maddrey's discriminant function ≥ 32) typically present with fever, jaundice, and abdominal tenderness. Alcohol abstinence is the cornerstone of therapy for AH and, in the milder forms, is sufficient for clinical recovery. Severe ASH may progress to multi-organ failure including acute kidney injury and infection. Thus, infection and renal failure have a major impact on survival and should be closely monitored in patients with severe ASH. Patients with severe ASH have a reported short-term mortality of up to 40%-50%. Severe ASH at risk of early death should be identified by one of the available prognostic scoring systems before considering specific therapies. Corticosteroids are the mainstay of treatment for severe ASH. When corticosteroids are contraindicated, pentoxifylline may be alternatively used. Responsiveness to steroids should be assessed at day 7 and stopping rules based on Lille score should come into action. Strategically, future studies for patients with severe ASH should focus on suppressing inflammation based on cytokine profiles, balancing hepatocellular death and regeneration, limiting activation of the innate immune response, and maintaining gut mucosal integrity.

Corticosteroids Do Not Increase the Risk of Infection Occurrence or Infection-Related Mortality amongst Patients with Severe Alcoholic Hepatitis: Presidential Poster

Purpose: Alcoholic hepatitis (AH) is a distinct syndrome amongst patients with chronic and active alcohol abuse, with about 40% mortality in severe (modified discriminant function or mDF≥32) disease. Corticosteroids (CS), currently first-line therapy for severe AH, provide only 50% survival benefit. Physicians often fear using CS in practice, for concern of infection in this sick population. We performed a meta-analysis of randomized controlled trials (RCT), assessing CS in severe AH with the aim of examining their impact on infection occurrence and infection-related mortality. Methods: An electronic database search revealed 15 RCT assessing CS in severe AH without infection at baseline. Of these, five were excluded (three without infection data, one without steroid free arm, and one duplicate study). Primary outcome was infection occurrence and infection-related mortality. Secondary outcomes were a) overall mortality, and b) mortality from gastrointestinal bleed (GIB) or from acute liver failure and/or hepatorenal syndrome (ALF/HRS). Data were pooled using fixed effects model and reported as odds ratio (OR) with 95% confidence interval (CI). I2 statistics and Egger's test were used to assess heterogeneity and publication bias, respectively. Results: Comparing 257 CS and 255 placebo treated patients, there was difference in occurrence of infection (19% vs. 20%, OR [95% CI]: 0.82 [0.5-1.37]). Five patients in CS and one in placebo group developed fungal infection, with two developing disseminated infection in CS arm. Other infections were similar in two groups: sepsis (21 vs. 23), urinary tract infection (9 vs. 11), pneumonia (7 vs. 9), SBP (6 vs. 6), and cellulitis (1 vs. 2). Median time to infection reported in four studies was 12-34 days in CS group, and 7-66 days in placebo group. A total of 179 patients (75 CS treated) died by 28 days of treatment. Mortality was lower with CS treatment (0.54 [0.36-0.81]), mainly due to prevention of death due to ALF/HRS (8% vs. 15%, 0.44 [0.22-0.86]) without difference from deaths from GIB (8% vs. 8%, 1.07 [0.54-2.13]) or from infection (10% vs. 13%, 0.88 [0.28-2.72]). Data were homogeneous without any publication bias. Of all the deaths, proportional mortality from infection, GIB, and ALF/HRS were no different between the two groups: 28% vs. 20%; 35% vs. 33%; and 27% vs. 37%, respectively. Conclusion: Corticosteroids improve short-term mortality in severe AH patients. This beneficial effect of CS is due to reduction in deaths from ALF/HRS without overall increase in the risk of infection or infection related mortality. To further optimize use of CS in severe AH, prospective studies are suggested examining antifungal prophylaxis and predictors of occurrence of infection.

Alcoholic Hepatitis: Steroids vs. Pentoxifylline

Alcoholic hepatitis (AH) remains a major cause of liver-related morbidity and mortality in the United States and is actually increasing in certain areas of Europe. Thus, there is a pressing need for new therapies/approaches. Major barriers for reducing morbidity, mortality, and costs of care include: lack of translational animal and human studies of new therapies for AH; limited trials of combination therapies in AH targeted at specific disease mechanisms (e.g., gut permeability, cytokines, oxidative stress); limited studies on non-invasive, non-mortality end points; few studies on mechanisms of steroid non-responsiveness; and inadequate prognostic indicators, to name only a few. In spite of these gaps, we have made major advances in understanding mechanisms for AH and appropriate therapies for AH. This article reviews mechanisms and rationale for use of steroids and pentoxifylline in AH and future directions in therapy.

Is histology required for the diagnosis of alcoholic hepatitis? a review of published randomised controlled trials

IntroductionThe need for liver biopsy to diagnose alcoholic hepatitis (AH) in the clinical setting remains controversial. Coagulopathy and/or ascites may preclude percutaneous biopsy and facilities for transjugular biopsy are not...

Alcoholic hepatitis 2010: A clinician’s guide to diagnosis and therapy

Alcoholic hepatitis (AH) remains a common and life threatening cause of liver failure, especially when it is severe. Although the adjective "acute" is frequently used to describe this form of liver injury, it is usually subacute and has been developing for weeks to months before it becomes clinically apparent. Patients with this form of alcoholic liver disease usually have a history of drinking heavily for many years. While certain aspects of therapy, mainly nutritional support and abstinence are well established, significant debate has surrounded the pharmacologic treatment of AH, and many institutions practice widely varying treatment protocols. In recent years a significant amount of literature has helped focus on the details of treatment, and more data have accumulated regarding risks and benefits of pharmacologic treatment. In particular, the efficacy of pentoxifylline has become increasingly apparent, and when compared with the risks associated with prednisolone, has brought this drug to the forefront of therapy for severe AH. This review will focus on the clinical and laboratory diagnosis and pharmacologic therapies that should be applied during hospitalization and continued into outpatient management. We conclude that the routine use of glucocorticoids for severe AH poses significant risk with equivocal benefit, and that pentoxifylline is a better, safer and cheaper alternative. While the full details of nutritional support lie beyond the scope of this article, nutrition is a cornerstone of therapy and must be addressed in every patient diagnosed with AH. Finally, while traditional psychosocial techniques play a major role in post-hospitalization care of alcoholics, we hope to make the medical clinician realize his or her role in reducing recidivism rates with early and frequent outpatient visits and with the use of baclofen to reduce alcohol craving.