Treatment Of Alcoholic Hepatitis Research Articles

Alcoholic Liver Disease from the Clinical Point of View

Liver disease is responsible for more than 55% of deaths resulting from alcohol abuse, while the prevalence of alcoholic liver disease (ALD) is closely correlated with per capita alcohol consumption. ALD represents a wide range of histological changes ranging from simple steatosis to heavier forms of liver injury including alcoholic hepatitis, cirrhosis and/or concurrent development of hepatocellular carcinoma. These alterations of the hepatic parenchyma do not necessarily reflect distinct stages of liver disease progression, but rather a continuum relating to histological changes that may be observed simultaneously in the same patient. The fact that only 35% of patients with heavy alcohol abuse develop advanced stages of liver disease, suggests that in the pathogenesis of ALD a number of other factors are involved that include gender, obesity, drinking patterns, dietary factors, non-sex-linked genetic factors and smoking. Also, long-term drinking can affect synergistically with hepatitis B or C and/or the human immunodeficiency virus, the non-alcoholic fatty liver disease and hepatic disorders such as hemochromatosis. The diagnosis of ALD is based on a combination of findings, including the history of significant alcohol consumption, the clinical evidence of the concomitant liver injury supported by the resultant histological, imaging and laboratory findings. A beneficial effect of alcoholic hepatitis treatment with corticosteroids is observed in patients with encephalopathy or with poor prognosis based on the various grading and prognostic systems of gravity, while the harmful effect is prominent in patients with milder disease, as they manifest an increased risk of infections compared with those not receiving corticosteroids. In patients with alcoholic hepatitis that cannot take corticosteroids for various reasons and in those with the onset of functional renal failure (“hepatorenal syndrome”), use of pentoxifylline is recommended.

Clinical effect of Mongolian drug Qinggan Jiuwei powder in treatment of alcoholic hepatitis

Clinical effect of Mongolian drug Qinggan Jiuwei powder in treatment of alcoholic hepatitis

Is there a role for pentoxifylline in the treatment of alcoholic hepatitis?

Abstract Despite better knowledge of the pathogenesis of severe alcoholic hepatitis (AH), corticosteroids are still the treatment recommended by clinical guidelines, pentoxifylline being the second-line option for non-responders to corticosteriods and for patients with contraindications. Pentoxifylline is a phosphodiesterase inhibitor with an anti-TNF effect and has been reported to reduce mortality and the incidence of hepatorenal syndrome in severe AH. After the first report, several studies, of distinct quality, have tested the efficacy of pentoxifylline in different scenarios. The conclusions of these studies are that pentoxifylline seems to improve survival in comparison to placebo but has lower efficacy than corticosteroids, with no improvement in survival when added to corticosteroids or in non-responders to steroid therapy. The role of pentoxifylline in severe alcoholic hepatitis is even more doubtful after the results of a very recent controlled study that showed no beneficial effect on survival at 1, 3 and 12 months of follow up, although a very recent network meta-analysis reported a beneficial effect of pentoxifylline alone or with corticosteroids on short-term survival. In conclusion, pentoxifylline has no clear beneficial effects in severe AH but could perhaps be used in patients with a contraindication to corticosteroids. However, the recommendations of clinical guidelines should be reconsidered and it is essential to search for new therapeutic targets for this disease.

Pharmacologic Treatment of Alcoholic Hepatitis: Examining Outcomes Based on Disease Severity Stratification

Maddrey discriminant function (MDF) score is a measure of disease prognosis in alcoholic hepatitis (AH) used to identify patients at highest risk of mortality and determine the need for initiation of pharmacologic treatment. The purpose of this study was to evaluate the effects of pharmacologic therapy for hospitalized AH patients as stratified by MDF score. A retrospective review of patients with an AH diagnosis admitted to a Methodist LeBonheur Healthcare adult hospital between 06/2009 and 06/2014 was conducted. Patients ≥18 years of age with an ICD-9 code for AH were evaluated. Of the 493 patients screened, 234 met the inclusion criteria, comprised of 62 patients with an MDF≥32 (treatment, n=42 vs. no treatment, n=20) and 172 patients with an MDF<32 (treatment, n=15 vs. no treatment, n=157). For the patients with an MDF≥32, there was no statistically significant difference between the treatment group vs. non-treatment group regarding 28-day mortality (31% vs. 11%, respectively; P=0.18) and 6-month mortality (45% treatment vs. 38% non-treatment; P=0.75). For the patients with an MDF <32, there was no statistically significant difference between the treatment group vs. non-treatment group regarding 28-day mortality (0% vs. 7%, respectively; P>0.99) and 6-month mortality (11% treatment vs. 13% non-treatment; P>0.99). There was no difference in incidence of acute kidney injury, hepatorenal syndrome, development of infection or hepatic encephalopathy between the treatment vs. non-treatment groups. Pharmacologic treatment showed no survival benefit, regardless of disease severity. Given the mortality risk seen in mild-moderate AH patients not receiving treatment and concern for a possible treatment ceiling effect in severe AH patients, more data are needed to adequately assess the utility of MDF in selecting appropriate candidates for AH treatment.

Is pentoxifylline effective in alcoholic hepatitis?

Steroidal therapy benefits patients with severe alcoholic hepatitis. However, steroid use is associated with severe side effects like infections and possibly, upper gastrointestinal bleeding. Pentoxifyllin, an inhibitor of Tumor Necrosis Factor has fewer side effects, but its effectiveness is not clear, nor its potential benefits as an adjunctive therapy to steroids. We used Epistemonikos database, which is mantained through searches in 19 databases, to find systematic reviews and their included primary studies. A structured summary was created using a predefined format that includes key messages, a summary of the body of evidence (presented as a matrix of evidence in Epistemonikos), and a summary of findings table using the GRADE approach, along with other factors that aid decision-making. Pentoxifyllin probably reduces mortality when compared with placebo. Pentoxifyllin could be less effective than steroid therapy for reducing mortality. Addition of pentoxifyllin to steroid therapy does not reduce mortality. Most practice guidelines have not taken into account an important portion of the existing evidence, even though their recommendations are in accordance with the present review.

Effects of Age, Sex, Body Weight, and Quantity of Alcohol Consumption on Occurrence and Severity of Alcoholic Hepatitis.

Only a minority of heavy drinking individuals develop alcoholic hepatitis (AH), for unclear reasons. We analyzed data from the Translational Research and Evolving Alcoholic Hepatitis Treatment cohort, consisting of subjects who drink heavily with normal results from liver tests (controls) and patients with AH. We examined risk factors for the development of AH including body mass index (BMI), drinking pattern and quantity, and sex. We compared data from 145 patients with AH and 124 controls based on BMI when they joined the cohort; groups were matched for sex and race. Drinking patterns were assessed using the timeline followback method, the Alcohol Use Disorders Identification Test, and the National Institute of Alcohol Abuse and Alcoholism 6-question survey. We performed univariable and multivariable analyses to assess the effects of these factors and their interaction in increasing the risk for AH. We also explored the association between PNPLA3 variants and AH. Cases with AH were older (47 vs 44 y; P= .03). For nearly all measures of quantity of alcohol consumed or frequency of binge drinking, controls drank more heavily than cases with AH. We did not find an association between BMI, sex, drinking patterns, and the presence of AH. Age and BMI were independent predictors for the severity of AH. When we analyzed cases and controls of European ancestry, the PNPLA3 single-nucleotide polymorphism rs738409 was associated with risk for AH (odds ratio, 1.89; P= .007). Compared with heavy drinkers without liver disease, subjects with AH consumed lower levels of alcohol and had less binge drinking, suggesting an increased sensitivity to the toxic effects of alcohol. The risk for AH may be associated with the PNPLA3 rs738409 polymorphism.

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.

Treatment of alcoholic hepatitis: is this a "dead-end"?

Summary from the trial. All patients were followed for 12 months or until their death with the exception of patients enrolled at the end of the trial. Th e primary endpoint was mortality at 28 days and secondary endpoints included mortality or liver transplantation at 90 days and aft er 1 year. Neither drug showed mid- (90 days) or long-term (12 months) survival benefi t. However, prednisolone was associated with an improvement in 28-day mortality with an odds ratio of 0.72 (95%CI 0.52-1.01; P=0.06). In multivariate analysis, baseline age, encephalopathy, white cell count, prothrombin ratio and levels of bilirubin, creatinine and urea were found to be additional signifi cant factors for mortality. In a secondary analysis adjusting for these prognostic variables the odds ratio for 28-day mortality among the patients who received prednisolone compared with those who did not was 0.61 (95%CI 0.41-0.91; P=0.02). Serious adverse events were reported in 42% of the patients with approximately half of them resulting in death. No signifi cant diff erences in the rate of adverse events were noted between treatment groups. However, infection occurred more frequently in patients who received prednisolone compared with those who did not (13% vs. 7%, P=0.002). Of note, infections were the main reason for death in this trial (24% of deaths). Finally, pentoxifylline was associated with numerically fewer cases of acute kidney injury.

Mallory Denk Body Formation in Alcoholic Hepatitis: The Pivotal Role of Interleukin-8 Signaling.

Mallory-Denk Bodies (MDBs) are prevalent in various liver diseases including alcoholic hepatitis (AH) and are formed in mice livers by feeding diethyl 1,4-dehydro-2,4,6-trimethyl-3,5-pyridine-dicarboxylate (DDC). The chemokine CXCL8, also known as interleukin-8 (IL-8) and its receptors are involved in oncogenesis and in tumor progression, invasion, and metastasis. We reported previously the marked upregulation of IL-8 signaling in AH and DDC fed mice with MDBs present by RNA sequencing (RNA-Seq) analyses. Central molecules including IL-8 and the chemokine (C-X-C motif) receptor 2 (CXCR2) of this pathway were significantly upregulated in the livers of DDC refed mice and human liver biopsies from AH livers. MDB containing balloon hepatocytes in AH livers have increased intensity of staining of the cytoplasm for both IL-8 and CXCR2. Taken conjointly, these data indicates a crucial role of IL-8 signaling during MDB formation, and IL-8 and CXCR2 may be targeted as biomarkers for personalized treatment of AH.

Effects of probiotics (cultured Lactobacillus subtilis/Streptococcus faecium) in the treatment of alcoholic hepatitis: randomized-controlled multicenter study.

Probiotics might reduce gut-derived microbial lipopolysaccharide (LPS) by restoring bowel flora in patients with alcoholic hepatitis (AH). We evaluated the therapeutic effects of probiotics in patients with AH. Between September 2010 and April 2012, 117 patients (probiotics 60 and placebo 57) were prospectively randomized to receive the 7 days of cultured Lactobacillus subtilis/Streptococcus faecium (1500 mg/day) or placebo. All patients were hospitalized and were not permitted to consume alcohol for the 7 days of the study. Liver function test, proinflammatory cytokines, LPS, and colony-forming units by stool culture were examined and compared after therapy. In both groups, the mean levels of aspartate aminotransferase/alanine aminotransferase, alkaline phosphatase, γ-glutamyl transpeptidase, bilirubin, and prothrombin time were significantly improved after 7 days of abstinence. In the probiotics group (baseline and after), albumin (3.5 ± 0.7 and 3.7 ± 0.6 g/dl, P=0.038) and tumor necrosis factor-α (121 ± 244 and 71 ± 123 pg/ml, P=0.047) showed differences. In addition, the number of colony-forming units of Escherichia coli was significantly reduced (435 ± 287 and 168 ± 210, P=0.002). In the placebo group, the level of LPS (1.7 ± 2.8 and 2.0 ± 2.7 EU/ml) was significantly increased. In the intergroup comparison, significant differences in the levels of tumor necrosis factor-α (P=0.042) and LPS (P=0.028) were observed between the groups. Immediate abstinence is the most important treatment for patients with AH. In addition, 7 days of oral supplementation with cultured L. subtilis/S. faecium was associated with restoration of bowel flora and improvement of LPS in patients with AH.

Effect and mechanism of ginsenoside Rg1 as an alcoholic hepatitis treatment in a rat model

To observe the effect of Rgl treatment on prognosis of alcoholic hepatitis using a rat model. Female Sprague-Dawley rats were radomly divided into four groups:unmodeled control, untreated model, Rgl-treated model, and dexamethasone (DXM)-treated model. The model groups were generated by intragastric injection of alcohol. The unmodeled control group was given an equal dosage of normal saline by the same route. After model establishment, the Rg1 treatment group and the DXM treatment group were administered a 120-hour treatment of Rgl or DXM; the unmodeled controls were administered normal saline on the same schedule. All rats were then fasted for 120 hours and venous blood samples were collected for detection of serum aspartate aminotransferase (AST), alanine transaminase (ALT), total bilirubin (TBil), albumin (Alb), tumor necrosis factor-alpha (TNFat) and interleukin 6 (IL-6). Markers of liver inflammation were measured by immunohistochemistry, western blotting, and real-time quantitative reverse transcription PCR. Fat and apoptosis indices were assessed by hematoxylin-eosin staining and TUNEL assay, respectively. The t-test and F test were used for statistical analyses. The model group showed remarkably more liver steatosis (over one-third of the tissue) than the unmodeled control group, indicating proper establishment of alcoholic liver disease in the modeled rats. The AST, ALT, TBil, and IL-6 levels were significantly higher in the untreated model group than in the Rgl-treated group and the DXM-treated group. The values were significantly different between the Rg1-treated group and the DXM-treated group:ALT, 69.19+/-8.00 U/L vs.102.88+/-5.16 U/L; TBil, 0.36+/-0.07 µmol/L vs.1.20+/-0.18 µmol/L; IL-6, 126.50+/-6.50 U/ml vs.169.19+/-7.68 U/ml; TNFa, 268.31+/-13.19 µg/L vs.318.94+/-7.87 µg/L (all P less than 0.05). Expression of caspase3 and caspase8 was significantly higher in the model group than in the Rgltreated group and the DXM-treated group (both P<0.05). The apoptosis index was significantly lower in the Rgltreated group and the DXM-treated group than in the model group (both P<0.05). The mRNA and protein expression of caspase3, caspase8 and NF-kB were significantly lower in the Rgl-treated group and the DXM-treated group than in the model group (allP less than 0.05), and the levels of all were significantly lower in the Rgl-treated group cornered to the DXM-treated group (all P<0.05). Conehision In rats with alcoholic hepatitis, Rg1 can significantly relieve pathological injury, improve liver function by blocking the apoptotic pathway, and inhibit release of inflammatory cytokines.

Combination therapy: New hope for alcoholic hepatitis?

Alcoholic hepatitis (AH) is a severe form of alcoholic liver disease with high mortality. The pathogenesis of AH is not fully understood, but it is generally believed that inflammation is a key factor leading to liver failure in AH. Steroids, which have broad immunosuppressive effects, have been used for the treatment of AH over the last forty years. Steroids elicit modest improvement in short-term survival rate in patients with severe AH, but also cause severe side effects. Several specific inflammatory targets (e.g., IL-1, LPS, and gut microbiota) are currently under investigation for the treatment of AH with the goal to obviate or reduce steroid administration. In addition to inflammation, impaired liver regeneration is another major cause of liver failure in AH, which deteriorates further after steroid treatment because inflammation plays a key role in promoting liver repair. Interleukin-22 (IL-22) is a promising drug for the treatment of AH because of its hepatoprotective and anti-fibrotic functions and relatively few known side effects. In addition, IL-22 treatment also ameliorates bacterial infection and kidney injury, two major complications associated with severe AH. IL-22 is currently under investigation in preclinical and clinical studies and may hold great promise for AH by providing more beneficial effects and fewer side effects than current therapies.

Corticosteroids and Bovine Colostrum in Treatment of Alcoholic Hepatitis ‘In Extremis’: A Pilot Study

Corticosteroids and Bovine Colostrum in Treatment of Alcoholic Hepatitis ‘In Extremis’: A Pilot Study

Screening and treatment of hepatitis B virus to prevent liver cancer in Africa.

Q Dr Thursz, can you tell us a little about your professional background to date? I initially trained in internal medicine and gastroenterology. I was given the opportunity to train in Hepatology at St Mary’s Hospital in 1990 by Prof Howard Thomas, who at that time was very active in the field of viral hepatitis and had also set up a liver transplant program. I undertook research at St Mary’s Hospital Medical School which subsequently became Imperial College between 1991 and 1994 studying immunogenetics of hepatitis B virus infection. I was fortunate enough to collaborate with Prof Adrian Hill from Oxford, which resulted in a number of high-impact publications on genetic susceptibility in hepatitis B virus infection [1–4]. I became lecturer and then senior lecturer at Imperial, working mostly on genetic susceptibility in viral hepatitis but also studying the natural history of hepatitis C virus infection. In 2002, I became secretary of the British Association for Study of the Liver, a position I held for 3 years. On the retirement of Prof Thomas in 2011, I was appointed head of the Section of Hepatology and Gastroenterology at Imperial College. In 2009, I was elected to the Governing Board of the European Association for Study of the Liver (EASL) as Vice-Secretary, and from 2011 to 2013 I served as SecretaryGeneral of EASL. My department is involved in a wide range of basic, translational and clinical research in liver disease. We have participated in many of the recent Phase II and III trials of direct acting antivirals for hepatitis C virus infection. I have just completed a large trial of treatment for alcoholic hepatitis evaluating the role of steroids and pentoxifylline.

Alcoholic liver disease: mechanisms of injury and targeted treatment.

Alcoholic liver disease (ALD) is a complex process that includes a wide spectrum of hepatic lesions, from steatosis to cirrhosis. Cell injury, inflammation, oxidative stress, regeneration and bacterial translocation are key drivers of alcohol-induced liver injury. Alcoholic hepatitis is the most severe form of all the alcohol-induced liver lesions. Animal models of ALD mainly involve mild liver damage (that is, steatosis and moderate inflammation), whereas severe alcoholic hepatitis in humans occurs in the setting of cirrhosis and is associated with severe liver failure. For this reason, translational studies using humans and human samples are crucial for the development of new therapeutic strategies. Although multiple attempts have been made to improve patient outcome, the treatment of alcoholic hepatitis is still based on abstinence from alcohol and brief exposure to corticosteroids. However, nearly 40% of patients with the most severe forms of alcoholic hepatitis will not benefit from treatment. We suggest that future clinical trials need to focus on end points other than mortality. This Review discusses the main pathways associated with the progression of liver disease, as well as potential therapeutic strategies targeting these pathways.

Alcoholic hepatitis: The pivotal role of Kupffer cells.

Kupffer cells play a central role in the pathogenesis of alcoholic hepatitis (AH). It is believed that alcohol increases the gut permeability that results in raised levels of serum endotoxins containing lipopolysaccharides (LPS). LPS binds to LPS-binding proteins and presents it to a membrane glycoprotein called CD14, which then activates Kupffer cells via a receptor called toll-like receptor 4. This endotoxin mediated activation of Kupffer cells plays an important role in the inflammatory process resulting in alcoholic hepatitis. There is no effective treatment for AH, although notable progress has been made over the last decade in understanding the underlying mechanism of alcoholic hepatitis. We specifically review the current research on the role of Kupffer cells in the pathogenesis of AH and the treatment strategies. We suggest that the imbalance between the pro-inflammatory and the anti-inflammatory process as well as the increased production of reactive oxygen species eventually lead to hepatocyte injury, the final event of alcoholic hepatitis.

Systemic Inflammatory Response Syndrome Predicts Acute Kidney Injury and In-Hospital Mortality Among Patients With Alcoholic Hepatitis

Introduction: Alcoholic hepatitis (AH) is associated with high in-hospital mortality. Onset of acute kidney injury (AKI) in AH is associated with in-hospital mortality (IHM). Systemic inflammatory response syndrome (SIRS) frequently occurs in AH independent of presence of infection. Data are limited on the association of SIRS with AKI and IHM. We performed this study to test our hypothesis that SIRS among AH patients is associated with AKI and IHM. Methods: Medical charts of patients admitted to our center (2006-2013) with discharge diagnosis of AH (ICD-9 code 571.1) were reviewed to identify patients meeting criteria for AH diagnosis and total bilirubin ≥5 mg/dL. Results: A total of 116 patients (mean age 46 years, 66% male, 80% white, 52% with underlying cirrhosis, and 9% concomitant HCV) met the criteria for AH diagnosis. Ninety-five patients had severe AH with discriminant function (DF) ≥32 and/or hepatic encephalopathy. AKI was observed in 64 (55%) patients with 44 on admission (20 outside hospital transfer [OHT]) and 20 during hospital stay. Patients with AKI compared to without AKI differed for male gender (77% vs. 52%, p=0.006), OHT (43% vs. 19%, p=0.007), hepatic encephalopathy (49% vs. 21%, p=0.007), white cell count (15% vs. 9%, p=0.0005), infection (61% vs. 40%, p=0.03), mean DF (33% vs. 19%, p<0.001), and mean MELD (33% vs. 19%, p<0.0001). AKI occurred in 83%, 53%, and 37% of patients with no SIRS (n=33), uninfected SIRS (n=63), and infected SIRS (n=6), respectively, p=0.06 (Figure 1). A total of 74 patients (48 with AKI) received medical treatment for AH. After controlling for age, gender, SIRS, infection, treatment, and DF, male gender, infected SIRS, and DF predicted AKI with HR 2.4 (95% CI 1.3-4.9), 3.2 (95% CI 1.1-9.1), and 1.01 (95% CI 1.005-1.02), respectively. Patients with AKI had higher in-hospital and overall mortality (6% vs. 48%, p≤0.0001; and 29% vs. 65%, p=0.0001) with more frequent need for ICU care (46% vs. 17%, p=0.001). AKI remained a strongest predictor of IHM with over 8-fold higher mortality in presence of AKI: 8.4 (95% CI 1.8-39). Other predictors were female gender and DF. Conclusion: AKI is a significant event in AH patients and negatively impacts the patient survival. Presence of SIRS and infection are strong predictors of development of AKI. Prospective well designed studies are suggested to assess interventions at the time of hospital admission in reducing the risk of AKI among patients with AH.

When are corticosteroids indicated in the treatment of alcoholic hepatitis?

When are corticosteroids indicated in the treatment of alcoholic hepatitis?

Liver transplantation for alcoholic liver disease

Alcoholic liver disease (ALD) is the major cause of life-threatening liver disease in Western countries. Abstinence from alcohol is the foundation of all treatment programmes for patients with ALD. Liver transplantation is a valuable option for patients with life-threatening ALD. Although the role of liver transplantation in the treatment of alcoholic hepatitis that is unresponsive to medical therapy is controversial, the latest prospective studies support this approach. No single measure gives a reliable estimate of the risk of drinking relapses before or after liver transplantation, but careful evaluation by an addiction specialist with a particular interest in transplant medicine is the best available approach. Survival, both on the waiting list and after the operation, is better in patients with ALD than in patients with HCV infection. Alcohol relapse may lead to liver damage and increased mortality, albeit usually after many years of renewed drinking. After liver transplantation, patients with ALD have increased rates of mortality and morbidity that are attributable to cardiovascular disease and new-onset cancers of the aerodigestive tract. The latter are probably linked to the high prevalence of smoking in this population. Cessation of smoking is thus an important goal in the care of patients with ALD after they have undergone liver transplantation.

Pentoxifylline-induced drug rash with eosinophilia and systemic symptoms (DRESS) in a patient with caffeine intolerance

Drug rash with eosinophilia and systemic symptoms (DRESS) is a severe drug reaction characterised by rash, eosinophilia and systemic involvement. We report a case of DRESS induced by pentoxifylline used for the treatment of severe alcoholic hepatitis, in a patient with longstanding caffeine intolerance. A history of intolerance to caffeine and other methylxanthines is listed as a contraindication to the use of pentoxifylline, yet this precaution is not mentioned in alcoholic hepatitis treatment guidelines. Prescribers should always seek a history of intolerance to caffeine and related compounds prior to use of pentoxifylline, as severe life threatening reactions can occur.