Biopsy-proven Alcoholic Hepatitis Research Articles

Histological characteristics in patients admitted to the hospital with alcoholic hepatitis complicated by acute-on-chronic liver failure

Objectives Alcoholic hepatitis (AH) is a frequent precipitating event for the development of acute-on-chronic liver failure (ACLF), a syndrome characterised by organ failures due to immune dysfunction. The histological features of this complication are not well characterized. We investigated whether ACLF has specific histological characteristics. Methods Prospective cohort study in consecutive adult patients admitted between 03-2008 and 04-2021 to a tertiary referral centre with suspected AH. Diagnosis of AH was based on clinical presentation and confirmed by transjugular liver biopsy. All biopsies were assessed by a dedicated liver pathologist, blinded for clinical data and outcome. Diagnosis of ACLF was based on EASL-CLIF criteria. Histological and clinical characteristics of patients with and without ACLF at baseline were compared. Results 184 patients with biopsy-proven AH were enrolled. Median time from hospital admission to transjugular biopsy was 4.5 days (IQR 2-8). At baseline, ACLF was present in 73 patients (39.7%). Out of the 110 patients without ACLF at baseline, 30 (27.3%) developed ACLF within 28 days (median 7.5 days (IQR 2-20)). At baseline, ductular bilirubinostasis (DB) was the only histological feature significantly more frequently present in patients with ACLF compared to patients without ACLF (50.7% vs. 30.6%, p = 0.003). No clear association between histological features and the development of ACLF later on could be demonstrated. Conclusions In this well-defined cohort of patients with biopsy-proven AH, DB was associated with the presence of ACLF. This finding fits with the pathophysiology of this syndrome, which is characterized by systemic inflammation and an increased risk of infections.

Prognostic Value of the Alcoholic Hepatitis Histologic Score in Korean Patients with Biopsy-Proven Alcoholic Hepatitis.

Background/AimsThe alcoholic hepatitis histologic score (AHHS) is a recently developed clinical model for predicting short-term mortality in Caucasian patients with alcoholic hepatitis (AH). The AHHS has not been extensively validated in other ethnic populations. This study validated the AHHS in a Korean patient cohort.MethodsWe conducted a prospective cohort study of hospitalized Korean patients with AH between January 2010 and August 2017. Histopathological findings were assessed to determine the AHHS in all study subjects. Histopathological risk factors were examined by Cox regression analysis to predict overall survival (OS). Kaplan-Meier curves were plotted to assess the diagnostic performance of the AHHS.ResultsWe recruited a total of 107 patients with biopsy-proven AH. None of the individual AHHS components were associated with 3-month mortality. However, the bilirubinostasis type and fibrosis severity were significantly associated with AH mortality beyond 6 months (all p<0.05, except fibrosis severity for 6-month mortality) and OS (all p<0.05). The modified AHHS classification as a binary variable (<5 vs ≥5) was also associated with OS (hazard ratio, 2.88; 95% confidence interval [CI], 1.50 to 5.56; p=0.002), and had higher predictive performance for OS (concordance index [C-index], 0.634; 95% CI, 0.561 to 0.707) than the original AHHS classification (mild vs moderate vs severe C-index, 0.577; 95% CI, 0.498 to 0.656). This difference was statistically significant (p=0.045).ConclusionsIn this prospective Korean AH cohort, the modified AHHS was significantly associated with OS. Therefore, the AHHS might be a useful histological prognosticator for long-term prognosis in patients with nonsevere AH.

Metabolomics Discloses a New Non-invasive Method for the Diagnosis and Prognosis of Patients with Alcoholic Hepatitis

Introduction and aims. Alcoholic hepatitis is the most severe manifestation of alcoholic liver disease. Unfortunately, there are still some unresolved issues in the diagnosis and management of this disease, such as the need of histological diagnosis, an accurate prognostic stratification, and the development of novel targeted therapies. The present study aimed at addressing these issues by means of metabolomics, a novel high-throughput approach useful in other liver diseases.Material and methods. 64 patients with biopsy-proven alcoholic hepatitis were included and compared with 26 patients with decompensated alcoholic cirrhosis without superimposed alcoholic hepatitis, which was ruled out by liver biopsy.Results. The comparison of the metabolic profiles of patients with alcoholic hepatitis and decompensated cirrhosis showed marked differences between both groups. Importantly, metabolic differences were found among alcoholic hepatitis patients when subjects were stratified according to 90-day survival. Based on these findings, two non-invasive signatures were developed. The first one allowed an accurate non-invasive diagnosis of alcoholic hepatitis (AUROC 0.932; 95% CI 0.901-0.963). The second signature showed a good performance in the prognostic stratification of patients with alcoholic hepatitis (AUROC 0.963; 95% CI 0.895-1.000).Conclusions. Signatures based on metabolomics allowed an accurate non-invasive diagnosis and prognostic stratification of alcoholic hepatitis. The differences observed in the metabolic profile of the patients according to the presence and severity of alcoholic hepatitis are related with different mechanisms involved in the pathophysiology of alcoholic hepatitis such as peroxisomal activity, synthesis of inflammatory mediators or oxidation. This information could be useful for the development of novel targeted therapies.

Metabolomics Discloses a New Non-invasive Method for the Diagnosis and Prognosis of Patients with Alcoholic Hepatitis

Introduction and Aims: Alcoholic hepatitis is the most severe manifestation of alcoholic liver disease. Unfortunately, there are still some unresolved issues in the diagnosis and management of this disease, such as the need of histological diagnosis, an accurate prognostic stratification, and the development of novel targeted therapies. The present study aimed at addressing these issues by means of metabolomics, a novel high-throughput approach useful in other liver diseases. Methods: 64 patients with biopsy-proven alcoholic hepatitis were included and compared with 26 patients with decompensated alcoholic cirrhosis without superimposed alcoholic hepatitis, which was ruled out by liver biopsy. Results: The comparison of the metabolic profiles of patients with alcoholic hepatitis and decompensated cirrhosis showed marked differences between both groups. Importantly, metabolic differences were found among alcoholic hepatitis patients when subjects were stratified according to 90-day survival. Based on these findings, two non-invasive signatures were developed. The first one allowed an accurate non-invasive diagnosis of alcoholic hepatitis (AUROC 0.932; 95% CI 0.901-0.963). The second signature showed a good performance in the prognostic stratification of patients with alcoholic hepatitis (AUROC 0.963; 95% CI 0.895-1.000). Conclusions: Signatures based on metabolomics allowed an accurate non-invasive diagnosis and prognostic stratification of alcoholic hepatitis. The differences observed in the metabolic profile of the patients according to the presence and severity of alcoholic hepatitis are related with different mechanisms involved in the pathophysiology of alcoholic hepatitis such as peroxisomal activity, synthesis of inflammatory mediators or oxidation. This information could be useful for the development of novel targeted therapies.

Alcohol abstinence in patients surviving an episode of alcoholic hepatitis: Prediction and impact on long-term survival.

Complete abstinence after an episode of AH positively impacts long-term survival. The combination of 2 variables easily obtained at admission might be useful to predict long-term abstinence after an episode of AH. Strategies aimed at promoting alcohol abstinence in these patients are necessary. (Hepatology 2017;66:1842-1853).

THU-334 - Alcoholic hepatitis histological scores predict short-term survival in Asian patients with biopsy-proven alcoholic hepatitis

THU-334 - Alcoholic hepatitis histological scores predict short-term survival in Asian patients with biopsy-proven alcoholic hepatitis

Enteral Nutrition for Severe Alcoholic Hepatitis

In the ongoing search for therapies that improve long-term survival in patients with acute alcoholic hepatitis, aggressive nutritional supplement has shown some promise. In the current multicenter study, researchers randomized 136 patients hospitalized with biopsy-proven alcoholic hepatitis to receive intensive enteral nutrition via feeding tube or conventional nutrition (according to local practice) for 14 days. Participants had new …

Alcoholic hepatitis histological score has high accuracy to predict 90-day mortality and response to steroids

Introduction/objectivesA histological classification system (AHHS) has been recently proposed to predict 90-day mortality in patients with alcoholic hepatitis (AH). We analyzed the spectrum of histological features in patients with AH and assessed the ability of AHHS for predicting both response to steroids and 90-day mortality. MethodsRetrospective study of patients admitted to our tertiary centre between 2010 and 2014 with biopsy-proven AH. Histological features were analyzed and AHHS value was calculated. Kaplan–Meyer curves were calculated to assess the ability of AHHS to predict response to steroids and 90-day mortality. ResultsWe included 34 patients (70.6% men, mean age 48.5±8.9 years). Transjugular liver biopsy was performed 3.5±2.9 days after admission. Presence of bilirubinostasis (p=0.049), degree of bilirubinostasis (p<0.001), absence of megamitochondria (p<0.001) and degree of polymorphonuclear infiltration (p=0.018) were significantly associated with higher mortality at 90 days. Patients who responded to steroids had a significantly lower AHHS value than non-responders (5.4±0.9 vs 8.1±1.1, p=0.003). AAHS value was significantly higher in patients who died compared to patients who survived at 90 days (9.0±0.7 vs 5.0±0.9, p<0.001). AHHS predicted response to steroids [AUROC 0.90 (CI95% 0.742–1.000), p=0.004] and 90-day mortality [AUROC 1.0 (CI95% 1.0–1.0), p<0.001] with high accuracy. ConclusionsIn this cohort of patients, presence and degree of bilirubinostasis, absence of megamitochondria and degree of PMN infiltration were significantly associated with 90-day mortality. AHHS had a high accuracy for predicting response to steroids and 90-day mortality in this cohort of patients.

Another Round? Liver Biopsy Determined the Diagnosis and Management in Patients With Alcohol Recidivism and Recurrent Acute Jaundice

Background: Reports of recurrent severe alcoholic hepatitis (AH) do not include confirmation by liver biopsy. We describe the clinical and histologic features of three patients with recurrent episodes of jaundice and suspected acute liver injury due to alcoholic recidivism. Methods: Evaluation of 120 patients with acute alcoholic liver injury included two with distinct hospitalizations between 2005 and 2012 for the recent onset of jaundice and a suspicion for severe alcoholic hepatitis (AH) defined by a discriminant function (DF) >32 or a MELD score of >18. A third patient later identified is included. Particular to these cases, a liver biopsy was performed during the index and a subsequent episode. Results: The clinical and histologic features for the first and subsequent episodes of acute alcoholic liver injury are presented in Table 1. Each patient had resolution of jaundice within 2-5 months after the first presentation. Recurrent jaundice in the context of alcohol recidivism occurred at an interval of 1-6 years. Patient #1 had cirrhosis and two episodes of biopsy-proven AH with histologic features of hepatocyte ballooning, Mallory-Denk bodies, and neutrophilic lobular inflammation. Treatment with corticosteroids for 7 days on both occasions resulted in partial responses with calculated Lille scores of 0.23 and 0.38, respectively. Patient #2 had two episodes of acute alcoholic fatty liver with cholestasis (AFLC), without histologic evidence of AH. Cholestasis, prominent macrovesicular fat, mild portal fibrosis, and mild lymphocytic lobular inflammation were present. Treatment was supportive. Patient #3 had an initial episode of self-limited jaundice due to AFLC followed by periods of recidivism and three recurrent episodes of jaundice over a period of >6 years. During the second recurrence, a liver biopsy showed AH. A calculated Lille score after 7 days of corticosteroids was 0.21, and 28-day treatment resulted in complete resolution of jaundice.Table 1: Clinical and histologic features of three patients with alcohol recidivism and recurrent episodes of acute jaundice due to alcoholic hepatitis (AH) or alcoholic fatty liver with cholestasis (AFLC)Conclusions: After a first episode of acute alcoholic liver injury, jaundice may recur in patients with alcohol recidivism. The histologic pattern of recurrent liver injury is not always the same. Liver biopsy remains important in evaluating recurrent episodes in order to distinguish between recurrence of the first injury, including AH, or other alcoholic liver diseases, like AFLC, that can have similar clinical presentations.

Commentary: scoring models for short‐term mortality in alcoholic hepatitis

Papastergiou et al. studied patients with biopsy-proven alcoholic hepatitis (AH) with regard to accuracy of scoring systems used to predict outcome and evaluate response to treatment.1 AH is distinguished by a plethora of scoring systems. Some, such as the discriminant function (DF),2 Glasgow alcoholic hepatitis score (GAHS)3 and the ABIC score,4 were developed specifically for use in AH. Others such as MELD have been co-opted from other areas of liver medicine.5 It has been clear for some time that all of these scores are fairly accurate in predicting short-term (28-day) and medium-term (90-day) mortality in AH.6-8 Papastergious' study is a helpful external validation of these scores, and is of particular interest as the cohort all had biopsy-proven AH. Many of the suggested models have been based on groups of patients where only a clinical diagnosis was made, thereby risking the inclusion of patients with other forms of hepatic decompensation. Although this study has validated the negative predictive value of these scoring systems many unanswered questions remain in the area of AH. We await with interest the United Kingdom randomised controlled trial evaluating therapies in AH.9 At present most groups use steroids in severe AH, and stop them if there is no biochemical response after 1 week. However, evidence for efficacy of steroids is disputed by standard meta-analysis and the duration of treatment remains unclear in those who respond. Although this current study does help our understanding of this serious disease, the key answers to its management will only come from randomised controlled trials. Declaration of personal and funding interests: None.

Nine scoring models for short‐term mortality in alcoholic hepatitis: cross‐validation in a biopsy‐proven cohort

BackgroundSeveral prognostic models have emerged in alcoholic hepatitis (AH), but lack of external validation precludes their universal use.AimTo validate the Maddrey Discriminant Function (DF); Glasgow Alcoholic Hepatitis Score (GAHS); Mayo End-stage Liver Disease (MELD); Age, Bilirubin, INR, Creatinine (ABIC); MELD-Na, UK End-stage Liver Disease (UKELD), and three scores of corticosteroid response at 1 week: an Early Change in Bilirubin Levels (ECBL), a 25% fall in bilirubin, and the Lille score.MethodsSeventy-one consecutive patients with biopsy-proven AH, admitted between November 2007-September 2011, were evaluated. The clinical and biochemical parameters were analysed to assess prognostic models with respect to 30- and 90-day mortality.ResultsThere were no significant differences in the areas under the receiver operating characteristics curve (AUROCs) relative to 30-day/90-day mortality: MELD 0.79/0.84, DF 0.71/0.74, GAHS 0.75/0.78, ABIC 0.71/0.78, MELD-Na 0.68/0.76, UKELD 0.56/0.68. One-week rescoring yielded a trend towards improved predictive accuracies (30-day/90-day AUROCs: 0.69–0.84/0.77–0.86). In patients with admission DF ≥32 (n = 31), response to corticosteroids according to ECBL, 25% fall in bilirubin and the Lille model yielded AUROCs of 0.73/0.73, 0.78/0.72 and 0.81/0.82 for a 30-day/90-day outcome respectively. All models showed excellent negative predictive values (NPVs; range: 86–100%), while the positive ones were low (range: 17–50%).ConclusionsMELD, DF, GAHS, ABIC and scores of corticosteroid response proved to be valid in an independent cohort of biopsy-proven alcoholic hepatitis. MELD modifications incorporating sodium did not confer any prognostic advantage over classical MELD. Based on excellent NPVs, the models are best to identify patients at low risk of death.

EPA-1391 – Study of the role of moderate alcohol consumption in the long-term prognosis of alcoholic hepatitis

Alcoholic hepatitis (AH) is the most severe form of alcoholic liver disease. Although it is commonly accepted that abstinence influences long-term survival, no studies have specifically investigated the impact and predicting factors of prolonged abstinence after an episode of AH. Here, we aimed at investigated which are the clinical, psicosocial, alcoologic parameters associated with long-term abstinence and its impact on survival. A series of 102 patients with biopsy-proven AH seen at the Hospital Clinic of Barcelona from 2000 to 2007 were included in the study. Patients were hospitalized and received standard medical care. We describe the independent association between amount of alcohol consumed and long-term abstinence. We evaluated the effect of short term and long-term abstinence on survival. 67.4% were male, and median age was 50 years. 50.5% of the study cohort remained abstinent during the follow up period, while 49.5% of the patients admitted alcohol use at some degree during follow up. A higher score on the High-Risk Alcoholism Relapse Scale increased risk of active drinking at follow-up. When stratified by amount of alcohol consumed after admission of acute alcoholic hepatitis, those with moderate survival had median survival time of 38.2 months compared to 26.4 months in patients with severe consumption. Early alcohol consumption after an episode of AH negatively impacts survival. The High risk Alcoholism Relapse Scale is a good predictor of long-term abstinence. Short-terms interventions in patients with AH are strongly recommended in this patient population.

Combination Therapy in Severe Alcoholic Hepatitis-Doesn't Really Work

Mathurin P, Louvet A, Duhamel A, Nahon P, Carbonell N, Boursier J, Anty R, Diaz E, Thabut D, Moirand R, Lebrec D, Moreno C, Talbodec N, Paupard T, Naveau S, Silvain C, Pageaux GP, Sobesky R, Canva-Delcambre V, Dharancy S, Salleron J, Dao T. Prednisolone with vs without pentoxifylline and survival of patients with severe alcoholic hepatitis: a randomized clinical trial. JAMA. 2013;310:1033-1041. Service des Maladies de l'Appareil digestif, Hopital Huriez, Lille, France. Importance: Prednisolone or pentoxifylline is recommended for severe alcoholic hepatitis, a life-threatening disease. The benefit of their combination is unknown. Objective: To determine whether the addition of pentoxifylline to prednisolone is more effective than prednisolone alone. Design, setting, and participants: Multicenter, randomized, double-blind clinical trial conducted between December 2007 and March 2010 in 1 Belgian and 23 French hospitals of 270 patients aged 18-70 years who were heavy drinkers with severe biopsy-proven alcoholic hepatitis, as indicated by recent onset of jaundice in the prior 3 months and a Maddrey score of at least 32. Duration of follow-up was 6 months. The last included patient completed the study in October 2010. None of the patients were lost to follow-up for the main outcome. Intervention: Patients were randomly assigned to receive either a combination of 40 mg of prednisolone once a day and 400 mg of pentoxifylline 3 times a day (n = 133) for 28 days, or 40 mg of prednisolone and matching placebo (n = 137) for 28 days. Main outcomes and measures: Six-month survival, with secondary end points of development of hepatorenal syndrome and response to therapy based on the Lille model, which defines treatment non responders after 7 days of initiation of treatment. Results: In intention-to-treat analysis, 6-month survival was not different in the pentoxifylline-prednisolone and placebo-prednisolone groups (69.9% [95% CI, 62.1%-77.7%] vs 69.2% [95% CI; 61.4%-76.9%], P = 0.91), corresponding to 40 vs 42 deaths, respectively. In multivariable analysis, only the Lille model and the Model for End-Stage Liver Disease score were independently associated with 6-month survival. At 7 days, response to therapy assessed by the Lille model was not significantly different between the 2 groups (Lille model score, 0.41 [95% CI, 0.36-0.46] vs 0.40 [95% CI, 0.35-0.45], P = 0.80). The probability of being a responder was not different in both groups (62.6% [95% CI, 53.9%-71.3%] vs 61.9% [95% CI, 53.7%-70.3%], P = 0.91). The cumulative incidence of hepatorenal syndrome at 6 months was not significantly different in the pentoxifylline-prednisolone and the placebo-prednisolone groups (8.4% [95% CI, 4.8%-14.8%] vs 15.3% [95% CI, 10.3%-22.7%], P = 0.07). Conclusion and relevance: In patients with alcoholic hepatitis, 4-week treatment with pentoxifylline and prednisolone, compared with prednisolone alone, did not result in improved 6-month survival. The study may have been underpowered to detect a significant difference in incidence of hepatorenal syndrome, which was less frequent in the group receiving pentoxifylline.

Prednisolone With vs Without Pentoxifylline and Survival of Patients With Severe Alcoholic Hepatitis

Prednisolone or pentoxifylline is recommended for severe alcoholic hepatitis, a life-threatening disease. The benefit of their combination is unknown. To determine whether the addition of pentoxifylline to prednisolone is more effective than prednisolone alone. Multicenter, randomized, double-blind clinical trial conducted between December 2007 and March 2010 in 1 Belgian and 23 French hospitals of 270 patients aged 18 to 70 years who were heavy drinkers with severe biopsy-proven alcoholic hepatitis, as indicated by recent onset of jaundice in the prior 3 months and a Maddrey score of at least 32. Duration of follow-up was 6 months. The last included patient completed the study in October 2010. None of the patients were lost to follow-up for the main outcome. Patients were randomly assigned to receive either a combination of 40 mg of prednisolone once a day and 400 mg of pentoxifylline 3 times a day (n=133) for 28 days, or 40 mg of prednisolone and matching placebo (n=137) for 28 days. Six-month survival, with secondary end points of development of hepatorenal syndrome and response to therapy based on the Lille model, which defines treatment nonresponders after 7 days of initiation of treatment. In intention-to-treat analysis, 6-month survival was not different in the pentoxifylline-prednisolone and placebo-prednisolone groups (69.9% [95% CI, 62.1%-77.7%] vs 69.2% [95% CI; 61.4%-76.9%], P = .91), corresponding to 40 vs 42 deaths, respectively. In multivariable analysis, only the Lille model and the Model for End-Stage Liver Disease score were independently associated with 6-month survival. At 7 days, response to therapy assessed by the Lille model was not significantly different between the 2 groups (Lille model score, 0.41 [95% CI, 0.36-0.46] vs 0.40 [95% CI, 0.35-0.45], P = .80). The probability of being a responder was not different in both groups (62.6% [95% CI, 53.9%-71.3%] vs 61.9% [95% CI, 53.7%-70.3%], P = .91). The cumulative incidence of hepatorenal syndrome at 6 months was not significantly different in the pentoxifylline-prednisolone and the placebo-prednisolone groups (8.4% [95% CI, 4.8%-14.8%] vs 15.3% [95% CI, 10.3%-22.7%], P = .07). In patients with alcoholic hepatitis, 4-week treatment with pentoxifylline and prednisolone, compared with prednisolone alone, did not result in improved 6-month survival. The study may have been underpowered to detect a significant difference in incidence of hepatorenal syndrome, which was less frequent in the group receiving pentoxifylline. clinicaltrials.gov Identifier: NCT01214226.

Acute Kidney Injury Is an Early Predictor of Mortality for Patients With Alcoholic Hepatitis

Alcoholic hepatitis (AH) is a severe condition with high mortality. To improve therapeutic strategies, it is important to identify factors that affect survival times. The age, bilirubin, international normalized ratio, and creatinine scoring system (also known as the ABIC scoring system) was developed previously to determine the prognosis of patients with AH. We studied effects of acute kidney injury (AKI) on survival of patients with AH. We retrospectively analyzed data from 103 patients with biopsy-proven AH. AKI was defined as an abrupt reduction (within 48 h) in kidney function that resulted in an absolute increase of at least 0.3 mg/dL (or a 50% increase) in serum levels of creatinine from baseline (the AKI network [AKIN] criteria). Twenty-nine patients (28%) developed AKI during hospitalization, with a median time to diagnosis of 3 days. Overall 90-day mortality was 23%, which was significantly higher among patients with AKI than those without (65% vs 7%; P < .0001). The age, bilirubin, international normalized ratio, and creatinine score (P < .0001) and development of AKI (P < .0001) were the most accurate independent predictors of 90-day mortality. The presence of systemic inflammatory response syndrome (P < .0001), serum bilirubin (P = .01), and international normalized ratio at admission (P = .03) were the most accurate predictors of AKI. Importantly, the AKIN criteria were more accurate than traditional criteria for renal failure (serum creatinine >1.5 mg/dL) in predicting 90-day mortality (area under the receiver operating characteristic, 0.83 vs 0.70, respectively; P = .02). Development of AKI reduces survival of patients with AH, in the short term. The AKIN criteria are useful and more accurate than traditional criteria in predicting mortality. Strategies to prevent AKI therefore should be considered in the management of patients with AH.

A New Scoring System for Prognostic Stratification of Patients With Alcoholic Hepatitis

Prognostic stratification of patients with alcoholic hepatitis (AH) may improve the clinical management and facilitate clinical trials. We aimed at developing a scoring system capable of providing prognostic stratification of patients with AH. Patients with biopsy-proven AH were prospectively included between 2000 and 2006. The biochemical, clinical, portal hemodynamic and histological parameters were evaluated. A Cox regression model was used for univariate and multivariate analyses. A predictive score was built using variables obtained at admission identified in the multivariate analysis. The resulting score was validated in an independent prospective cohort. In total, 103 patients with biopsy-proven AH were included in the study cohort. Age, serum bilirubin, serum creatinine, and international normalized ratio (INR) independently predicted 90-day mortality. We generated the Age, serum Bilirubin, INR, and serum Creatinine (ABIC) score: (age x 0.1) + (serum bilirubin x 0.08) + (serum creatinine x 0.3) + (INR x 0.8). The area under the curve (AUC) was 0.82. Using the Kaplan-Meier analysis with the cutoff values of 6.71 and 9.0, we identified patients with low, intermediate, and high risk of death at 90 days (100%, 70%, and 25% of survival rate, respectively). Using the same cutoff values, the ABIC score also stratified patients according to their risk of death at 1 yr. These results were validated by a confirmatory cohort (N = 80). The ABIC score is a new tool that allows the stratification of risk of death in patients with AH at 90 days and 1 yr. This score can help improve the management of these patients and also help to perform clinical trials.

Combined polymorphisms of tumour necrosis factor alpha and interleukin-10 genes in patients with alcoholic hepatitis

The development and progression of alcoholic hepatitis are controlled by an extensive cytokine network which involves pro-inflammatory and anti-inflammatory cytokines. Genetic variations determining production of these cytokines have been described and the susceptibility to the disease may be determined by an imbalance in the expression of several candidate genes. We have studied biallelic single nucleotide polymorphisms at positions (-308) and (-238) in the promoter region of the pro-inflammatory tumour necrosis factor alpha (TNF-alpha) and at positions (-1,082) and (-592) in the promoter of anti-inflammatory interleukin-10 (IL-10) in 134 patients with severe biopsy-proven alcoholic hepatitis and 145 healthy subjects. The frequency distribution of isolated cytokine genotypes did not differ between the two groups. The combination of at least one A or A allele for TNF-alpha, associated with a TNF-alpha high-producer phenotype, and one A or A allele for IL-10, associated with an IL-10 low-producer phenotype, was less frequent in patients (20.9 vs 33.8%, P=0.016, OR (95% CI)=0.52 (0.30-0.89)). The same combination in patients was associated with a higher risk of septic complications (32.5 vs 16.0%, P=0.031, OR (95% CI)=1.79 (1.07-6.00)) but not with in-hospital mortality. We have not found any relationship between the isolated polymorphisms and the risk of alcoholic hepatitis. Moreover, the imbalance between the pro-inflammatory and anti-inflammatory responses leading to high TNF-alpha production and low IL-10 was uncommon in alcoholic hepatitis. However, patients with this particular genotype appeared more susceptible to severe septic complications.

Circulating concentrations of interleukin‐18, interleukin‐18 binding protein, and γ interferon in patients with alcoholic hepatitis

Alcoholic hepatitis (AH) is associated with dysregulated inflammatory and immune responses. interleukin-18 (IL-18), described as gamma interferon (gammaIFN)-inducible factor, and its natural antagonist, IL-18 binding protein (IL-18 BP), has not been fully studied in patients with AH. Thus, our aim was: (i) to determine plasma values of IL-18, IL-18 BP, gammaIFN, and tumor necrosis factor alpha (TNF)-alpha in patients hospitalized for biopsy-proven AH; (ii) to correlate these cytokines with the severity of AH, as assessed by Maddrey's discriminant function (DF), the degree of liver failure using the Child-Pugh score and blood neutrophils; (iii) to compare cytokines values in survivors and non-survivors. Cytokines were measured using specific immunoassays within 7 days of admission. The diagnosis of AH was based on histology in all cases. We studied 43 cirrhotic patients with a Maddrey's DF>/=32 (severe AH), 29 patients with a score <32 (non-severe AH), 12 patients with abstinent alcoholic cirrhosis, and 10 healthy subjects. IL-18 and TNFalpha were increased in severe AH as compared with healthy subjects. Plasma IL-18 BP was elevated in patients with severe and non-severe AH as compared with healthy subjects. gammaIFN did not differ between groups. In patients with severe and non-severe AH, IL-18, IL-18 BP, TNFalpha, but not gammaIFN, were positively correlated to DF and Child-Pugh score. Neither IL-18 nor IL-18 BP correlated to TNFalpha. Patients who died (n=10) during the hospitalization had higher IL-18 BP and TNFalpha at admission as compared with survivors (322 [172-504] vs 222 [109-441] ng/ml; 7.5 [2.2-17.3] vs 3 [0.6-20] pg/ml, P<0.01, respectively). In cirrhotic patients with AH, IL-18, IL-18 BP, and TNFalpha correlate to the hepatitis severity and to the degree of liver failure. High IL-18 BP and TNFalpha at hospital admission in non-survivors suggest it may be of prognostic value.

Soluble TNF-R1, but not tumor necrosis factor alpha, predicts the 3-month mortality in patients with alcoholic hepatitis

Background/Aims In alcoholic hepatitis (AH), soluble TNFα receptor-1 (sTNF-R1) is increased. Elevated TNFα predicts mortality, but infection influences TNFα values. In patients with AH, we determined the prognostic value of TNFα, sTNF-R1, and lipopolysaccharide binding protein (LBP) and CD14, both involved in endotoxemia-associated inflammation. Methods One hundred and eight cirrhotic patients (Pugh score 10 [6–13]) and biopsy-proven AH (Maddrey's DF <32: n=46; ≥32: n=62) without associated infection were included within 8 days of admission and followed-up for 3 months. Cytokines were measured using specific immunoassays. Patients with severe AH received steroids. Results Twenty four patients died at a median time of 35 days (range: 3–89). The overall survival was 78%. Multivariate Cox regression analysis showed that sTNF-R1 was an independent predictor of mortality, (OR 4.33: 95% CI [1.12–16.75]). Pugh's score ( P=0.618), Maddrey's DF ( P=0.182), creatinine ( P=0.197), TNFα ( P=0.319), LBP ( P=0.362), and CD14 ( P=0.347) were not related to survival. Conclusions In patients with AH, sTNF-R1 measured at admission is an independent predictor of survival at 3 months. Provided that TNF-R1 mediates the cytotoxic actions of TNFα, these results support the concept of dysregulated TNFα metabolism in AH.

Soluble TNF-R1, but not TNF$alpha;, predicts the 3-month mortality in patients with alcoholic hepatitis*1

Background/Aims In alcoholic hepatitis (AH), soluble TNFα receptor-1 (sTNF-R1) is increased. Elevated TNFα predicts mortality, but infection influences TNFα values. In patients with AH, we determined the prognostic value of TNFα, sTNF-R1, and lipopolysaccharide binding protein (LBP) and CD14, both involved in endotoxemia-associated inflammation. Methods One hundred and eight cirrhotic patients (Pugh score 10 [6–13]) and biopsy-proven AH (Maddrey's DF <32: n=46; ≥32: n=62) without associated infection were included within 8 days of admission and followed-up for 3 months. Cytokines were measured using specific immunoassays. Patients with severe AH received steroids. Results Twenty four patients died at a median time of 35 days (range: 3–89). The overall survival was 78%. Multivariate Cox regression analysis showed that sTNF-R1 was an independent predictor of mortality, (OR 4.33: 95% CI [1.12–16.75]). Pugh's score (P=0.618), Maddrey's DF (P=0.182), creatinine (P=0.197), TNFα (P=0.319), LBP (P=0.362), and CD14 (P=0.347) were not related to survival. Conclusions In patients with AH, sTNF-R1 measured at admission is an independent predictor of survival at 3 months. Provided that TNF-R1 mediates the cytotoxic actions of TNFα, these results support the concept of dysregulated TNFα metabolism in AH.