Outcome In Severe Alcoholic Hepatitis Research Articles

Severity of Acute Portal Hypertension Determines the Clinical Outcomes in Severe Alcoholic Hepatitis.

Severe alcohol-associated hepatitis (SAH) presenting as acute-on-chronic liver failure (ACLF) has high mortality. Severe hepatic inflammation and ongoing hepatocellular cell death lead to rapid rise in portal pressure, a hyperdynamic circulation that might precipitate infections and organ failures. Consecutive SAH patients were classified based on baseline HVPG measurement as 6to < 12mmHg, 12to < 20mmHg, and ≥ 20mmHg. We analyzed portal hypertension severity in relation to fibrosis stage, ACLF at presentation, response to prednisolone, severity scores(MELD and Maddrey's Discriminant Function, mDF), and 90-day mortality. Of 819 SAH patients (94.6% ACLF, 85.4% histological cirrhosis, median MELD and mDF scores 25 and 66, respectively), 250(30.5%) had HVPG ≥ 20mmHg. Patients with HVPG ≥ 20mmHg more often had large esophageal varices (25.2%vs.13.2%; p-0.001), higher baseline MELD (27.1 ± 5.6vs.25.3 ± 5.2; p-0.001), and mDF(76.1 ± 16vs.68.4 ± 15.1; p-0.01) scores. No patient without ACLF had HVPG ≥ 20mmHg. Moreover, during hospital course these patients had higher incidence of variceal bleed (17.2%vs.8.8%; p-0.001), acute kidney injury (36.4%vs.25.3%; p-0.001), and spontaneous bacterial peritonitis (6.4%vs.3.5%; p-0.05). Of 412(50.3%) eligible patients treated with prednisolone, 69.2% showed response at day 7(Lille's score < 0.45). 90-day mortality was 27.6%; and baseline MELD > 25.5[HR 1.78], HVPG ≥ 20mmHg [HR 1.86], the presence of HE[HR 1.63], and prednisolone ineligibility due to sepsis[HR 1.27] were independent predictors. Mortality was unrelated to varices grade, variceal bleed, and histological cirrhosis. Repeat HVPG performed in 114(19.2%) patients after a median of 5.2months showed significant decrease (3.6mmHg; p-0.001) which correlated with improvement in MELD score(13points; p-0.05). Development of ACLF and complications in SAH are likely a result of acute rise in HVPG. "High-risk" SAH are SAH patients with HVPG ≥ 20mmHg in the presence of ascites. Understanding the drivers for acute rise in portal pressure in SAH ACLF might help introduction of newer therapies.

OS-006-YI - Plasma multi-omics outlines association of urobilinogen with corticosteroid non-response, inflammation, intestinal permeability and outcome in severe alcoholic hepatitis

OS-006-YI - Plasma multi-omics outlines association of urobilinogen with corticosteroid non-response, inflammation, intestinal permeability and outcome in severe alcoholic hepatitis

THU083 - Temporal change in the plasma metabolome profile is indicative of outcome in severe alcoholic hepatitis

THU083 - Temporal change in the plasma metabolome profile is indicative of outcome in severe alcoholic hepatitis

Dysregulated Lipid Transport Proteins Correlate With Pathogenesis and Outcome in Severe Alcoholic Hepatitis.

Severe alcoholic hepatitis (SAH) has high mortality. Dysregulated lipid transport and metabolism in liver/macrophages contributes to disease pathophysiology. Paraoxonase/arylesterase 1 (PON1), a liver‐specific enzyme, inhibits oxidation of phospholipids and prevents lipid‐mediated oxidative damage. However, its functional contribution in macrophage‐mediated hepatic injury warrants elucidation. Plasma proteome of patients with SAH (n = 20), alcoholic cirrhosis (n = 20), and healthy controls was analyzed. Dysregulated pathways were identified, validated, and correlated with severity and outcomes in 200 patients with SAH. Tohoku‐Hospital‐Pediatrics‐1 (THP1)‐derived macrophages were treated with plasma from study groups in the presence/absence of recombinant PON1 and the phenotype; intracellular lipid bodies and linked functions were evaluated. In patients with SAH, 208 proteins were >1.5 fold differentially regulated (32 up‐regulated and 176 down‐regulated; P < 0.01).Validation studies confirmed lower levels of lipid transporter proteins (Pon1, apolipoprotein [Apo]B, ApoA1, ApoA2, and ApoC3; P < 0.01). Low PON1 levels inversely correlated with severity and mortality (r2 > 0.3; hazard ratio, 0.91; P < 0.01) and predicted nonsurvivors (area under the receiver operating characteristic curve, 0.86; cut‐off, <18 μg/mL; log rank, <0.01). Low PON1 levels corroborated with increased oxidized low‐density lipoprotein levels, intracellular lipid bodies, lipid uptake, lipid metabolism, biosynthesis, and alternative macrophage activation genes in nonsurvivors (P < 0.01). Importantly, in vitro recombinant PON1 treatment on THP1 macrophages reversed these changes (P < 0.01), specifically by alteration in expression of clusters of differentiation 36 (CD36) and adenosine triphosphate‐binding cassette subfamily A1 (ABCA1) receptor on macrophages. Conclusion: Lipid transport proteins contribute to the pathogenesis of SAH, and low PON1 levels inversely correlate with the severity of alcoholic hepatitis and 28‐day mortality. Restitution of circulating PON1 may be beneficial and needs therapeutic evaluation in patients with SAH.

960 Revised Lille Score for Predicting 90 Days Mortality in Severe Alcoholic Hepatitis

INTRODUCTION: Iron is an essential micronutrient which circulates bound to transferrin for tissue distribution. Liver is the main site for transferrin synthesis and its dysfunction can alter iron homeostasis resulting in oxidative stress. Recent studies showed that transferrin saturation is an independent predictor of mortality in patients with decompensated cirrhosis. We aim to evaluate the prognostic efficacy of transferrin saturation and revised Lille score to predict 90-days mortality in patients with severe alcoholic hepatitis. METHODS: We retrospectively reviewed the electronic medical records of patients diagnosed with severe alcoholic hepatitis (SAH) who received prednisolone therapy. Demographic and biochemical data at diagnosis and day 4 was collected. Univariate logistic regression for all variables included in Lille score along with ferritin and transferrin percent was performed. A revised Lille score was created based on results of univariate analysis. The efficacy of revised Lille score was then tested against Lille score on day 4 with receiver operating characteristics (ROC) analysis and Kaplan-Meier survival analysis by dichotomization per optimal cut-offs. RESULTS: In our cohort of 80 patients with SAH, 12(13.3%) patients died within 90 days. Apart from all parameters included in the Lille score, transferrin saturation was identified as an independent predictor of 90-days mortality on univariate analysis (Table 1). Revised Lille score was generated by the formula mentioned below. The ROC analysis for the prediction of 90-day mortality of Day 4 revised Lille score revealed a higher AUC of 0.8419 in comparison to Day 4 Lille score that had a lower AUC of 0.6985 (Table 1). With the optimal cut-off value of 5, the revised Lille score sub-classified patients into low and high-risk (HR = 21.05, P &lt; 0.004) groups (Figure 2). Revised Lille score = 2.15 × Lille score + 0.06 × Transferrin saturation CONCLUSION: In conclusion, revised Lille score at fourth day can be utilized to predict mortality at 90 days. When using a cut-off of 5, patients can be subclassified into low and high-risk groups with a sensitivity and specificity of 97.95% and 35.48 respectively. We propose that revised Lille score should be compared with Lille score in predicting outcomes in SAH. Moreover, patients with elevated transferrin saturation have a high mortality.

Modification Patterns of Urinary Albumin Correlates With Serum Albumin and Outcome in Severe Alcoholic Hepatitis.

Albumin modifications and deranged functions are well documented in serum of severe alcoholic hepatitis (SAH). We investigated whether urinary albumin (u-Alb) can serve as surrogate marker of circulatory albumin phenotype, functionality, and could predict outcome in SAH patients. Baseline serum and urine samples from 100 SAH, 20 alcoholic cirrhosis, and 20 healthy controls were subjected to u-Alb, ischemia modified albumin (IMA), IMA to albumin ratio (IMAr), advanced oxidation protein products, advanced glycation end-products, albumin-binding capacity determination. In addition, SAH urinary samples were also analyzed at day 4 and day 7 to predict nonresponse to corticosteroid therapy. Urine and serum levels of IMA, advanced oxidation protein products and advanced glycation end-products were higher (P<0.05) in SAH versus alcoholic cirrhosis and healthy controls. IMAr was low in urine but high in serum of SAH (P<0.05). Albumin-binding capacity was lower (P<0.05) in both urinary and serum albumin of SAH. Urinary and serum albumin parameters showed direct correlation, whereas IMAr showed inverse correlation (cc>0.2, P<0.05). Baseline u-Alb level was significantly higher in SAH, and was correlated directly with corticosteroid treatment outcome and 12-month mortality in SAH. Baseline u-Alb showed an area under the receivers operating curve analysis of 0.7 and a hazard ratio of 1.23 for prediction of 12-month mortality in SAH. Baseline u-Alb level >9.0 mg/dL was associated with reduced 12-month survival in SAH (log rank <0.01). u-Alb modifications are reflective of serum albumin modifications. Further baseline u-Alb levels could be exploited to predict steroid response and mortality in SAH patients.

Efficacy of Granulocyte Colony‐stimulating Factor in the Management of Steroid‐Nonresponsive Severe Alcoholic Hepatitis: A Double‐Blind Randomized Controlled Trial

Severe alcoholic hepatitis (SAH) is often a progressive disease with high mortality and limited steroid responsiveness. Management options of steroid nonresponsive SAH (day 7 Lille score > 0.45) are limited. We assessed the efficacy and safety of granulocyte colony-stimulating factor (G-CSF) in steroid nonresponders. A randomized, double-blind, single-center trial (NCT01820208) was conducted between March 2013 and June 2016 in patients with histologically proven SAH, nonresponsive to 40 mg/day of prednisolone were randomized to G-CSF (12 doses, 300 μg each in 28 days) or placebo. Responders were continued with prednisolone. Of the 430 patients with SAH, 132 received steroid therapy. Of these, 33 (25%) were nonresponders and were randomized to G-CSF or placebo (14 in each group after exclusions). The baseline characteristics of both groups were comparable. The 28-day mortality was comparable between the groups (21.4%, G-CSF; 28.6%, placebo; P = 0.69). At 90 days, in the G-CSF but not in the placebo group, the Model for End-Stage Liver Disease reduced from 24.6 ± 3.9 to 19.4 ± 3.7 (P = 0.002) and Maddrey's discriminant function from 74.8 ± 22.8 to 57.4 ± 31 (P = 0.26). Infections were less common (28% versus 71%; P < 0.001) with lower 90-day mortality (35.7% versus 71.4%; P = 0.04) in the G-CSF than in the placebo group. On Cox regression analysis, receiving G-CSF (hazard ratio, 0.37; SD, 0.14-0.98; P = 0.04), and high baseline serum creatinine (hazard ratio, 4.12; SD, 1.7-10.3; P = 0.002) predicted day-90 outcomes in steroid nonresponsive SAH. Patients tolerated G-CSF without any major adverse events. Conclusion: Approximately one-quarter of patients with SAH do not respond to corticosteroid therapy. Administration of G-CSF is safe and helps to reduce the disease severity and 90-day mortality in these patients.

A Novel Scoring System to Predict Outcomes in Severe Alcoholic Hepatitis

Current tools to predict survival in patients with severe alcoholic hepatitis (SAH), such as the model for end-stage liver disease (MELD) and Lille

Outcomes after index hospital admission for decompensated alcohol-related cirrhosis versus severe alcoholic hepatitis: a retrospective cohort study

BackgroundWe have previously described outcomes in severe alcoholic hepatitis, identifying abstinence after hospital discharge as the only independent predictor of long-term survival. The outcome of patients presenting with other forms of decompensated alcohol-related liver disease is unknown. Our aim was to assess predictors of inpatient and long-term survival in patients admitted with decompensated alcohol-related cirrhosis compared with those with severe alcoholic hepatitis. MethodsA retrospective case-note review was performed for all index hospital admissions with alcoholic-related liver disease between April 1, 2005, and Dec 31, 2011. Patients with decompensated alcohol-related cirrhosis (Child-Pugh score ≥7 and bilirubin <80 mmol/L) were compared with a previously studied cohort with severe alcoholic hepatitis admitted over the same time period (discriminant function ≥32, corroborated by biopsy results where available). Predictors of inpatient survival were determined using binary logistic regression, and the Kaplan-Meier method was used to estimate long-term survival. Findings177 patients were studied (73 decompensated alcohol-related cirrhosis, 104 severe alcoholic hepatitis). In decompensated alcohol-related cirrhosis, the independent determinants of inpatient mortality were hospital-acquired infection (odds ratio 20·2, 95% CI 3·5–118; p=0·001) and hepatic encephalopathy (9·3, 1·8–47; p=0·007). Overall median survival was similar in both groups (26 months [IQR 12·8–39·2] in decompensated alcohol-related cirrhosis vs 23 [10·6–35·4] in severe alcoholic hepatitis, p=0·872) with similar abstinence rates at last follow-up (41·1% vs 34·6%, p=0·431). In severe alcoholic hepatitis, abstinence at last follow-up was the only predictor of survival (3 year survival 75·2% in abstainers vs 33·2% in continued drinkers, p=0·012). However, in decompensated alcohol-related cirrhosis, abstinence did not predict long-term survival (median survival 36 months [IQR 22·3–49·7] in abstainers vs 38 [9·9–66·1] in continued drinkers, p=0·949). InterpretationInpatient mortality in decompensated alcohol-related liver disease was predicted by hospital-acquired infection and hepatic encephalopathy. Long-term survival in decompensated alcohol-related cirrhosis did not significantly improve with abstinence, which is in contrast to severe alcoholic hepatitis, and this suggests a reduced scope for disease reversibility thereby mandating earlier assessment for liver transplantation. FundingNone.

High alcohol relapse rate linked to poor survival in patients with alcoholic hepatitis

British Journal of Hospital MedicineVol. 74, No. 8 Clinical newsHigh alcohol relapse rate linked to poor survival in patients with alcoholic hepatitisSumita VermaSumita VermaSearch for more papers by this authorSumita VermaPublished Online:18 Nov 2013https://doi.org/10.12968/hmed.2013.74.8.429AboutSectionsView articleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareShare onFacebookTwitterLinked InEmail View article References Potts JR Goubet S Heneghan MA Verma S (2013) Determinants of long-term outcome in severe alcoholic hepatitis. Aliment Pharmacol Ther 23 July (Epub ahead of print) Crossref, Medline, Google Scholar FiguresReferencesRelatedDetails 1 August 2013Volume 74Issue 8ISSN (print): 1750-8460ISSN (online): 1759-7390 Metrics History Published online 18 November 2013 Published in print 1 August 2013 Information© MA Healthcare LimitedPDF download

Determinants of long-term outcome in severe alcoholic hepatitis

Although short-term outcome in severe alcoholic hepatitis (SAH) is well described, its long-term course remains uncharacterised. To assess determinants of long-term outcome in SAH. Data were recorded from a cohort with SAH (admission Discriminant Function (DF) ≥32). Kaplan-Meier (KM) and Cox proportional hazards survival analyses were performed to determine predictors of outcome. One hundred and nine patients were included; 63.3% male, aged 49.6±9.4years with median follow-up of 40.7months (95% CI 37.2-44.3). Median DF was 58, 86.2% had cirrhosis and 65.1% received corticosteroids and/or pentoxifylline. Overall mortality was 57.8%, 96.8% of deaths being liver-related and 65.1% occurring after the index hospitalisation. Estimated 5-year survival was 31.8%. Hepatorenal syndrome was the only baseline factor independently associated with mortality (HR 3.78, 95% CI 1.98-7.19, P<0.0001), although it predicted short-term, rather than long-term outcome (median survival 0.52months, 95% CI 0.43-0.61). Of the 87 patients (79.8%) who survived index hospitalisation, 65.1% experienced recidivism. Abstinence at last follow-up remained the only independent predictor of survival in multivariate analysis (HR 0.370, 95% CI 0.168-0.818, P=0.014). Five-year survival was higher in abstainers (75.3%) compared with relapsed and continued drinkers (26.8% and 21.0%, respectively, P=0.005). However, the survival benefit from abstinence only became statistically significant at 18months postdischarge (HR 2.714, 95% CI 0.995-7.404, P=0.051). Estimated 5-year survival after index hospitalisation with SAH is 31.8% with alcohol relapse occurring in two-thirds of patients. Abstinence remains the only independent predictor of long-term survival. Novel strategies to improve abstinence after admission with SAH are urgently needed.

PTU-118 Long-Term outcome in Severe Alcoholic Hepatitis

IntroductionAlthough short-term outcome in severe alcoholic hepatitis (SAH) is well described, its long-term course is largely unknown. Our aim was to assess long-term outcome in SAH.MethodsCohort study of patients with...

In vitro steroid resistance correlates with outcome in severe alcoholic hepatitis

Steroids improve the outcome in alcoholic hepatitis (AH), but up to 40% of patients fail to respond adequately. Interleukin-2 (IL-2) exacerbates steroid resistance in vitro. We performed a prospective study to determine if intrinsic steroid sensitivity correlates with response to steroids in individuals with severe AH and if IL-2 receptor blockade can reverse this. Peripheral blood mononuclear cells (PBMCs) were isolated from 20 patients with AH and a Maddrey's score >32. Patients were treated with oral prednisolone plus full supportive measures. Clinical resistance to oral steroid treatment was defined as a drop in serum bilirubin of <25% within 7 days or death within 6 months. In vitro steroid resistance was measured in PBMC using the dexamethasone suppression of lymphocyte proliferation assay and repeated after the addition of the anti-IL-2 receptor (anti-CD25) monoclonal antibody, basiliximab. Suppression of lymphocyte proliferation <60% was considered to indicate steroid resistance. In all, 82% (9/11) of in vitro steroid-resistant patients were dead at 6 months as compared to 21% (2/9) of steroid-sensitive patients (P = 0.03). Similarly, 91% (10/11) of in vitro steroid-resistant patients failed to show a significant fall in bilirubin at day 7 as compared to 44% (4/9) of steroid-sensitive patients (P < 0.05). Basiliximab improved the maximal proliferation count in 91% (10/11) of in vitro steroid-resistant patients (P = 0.003). Clinical outcome of steroid therapy in this patient cohort correlated with in vitro steroid resistance. IL-2 blockade improved in vitro steroid sensitivity. This suggests that intrinsic lack of steroid sensitivity may contribute to poor clinical response to steroids in severe AH. IL-2 receptor blockade represents a possible mechanism to overcome this.

Increasing dimethylarginine levels are associated with adverse clinical outcome in severe alcoholic hepatitis

Previous studies suggest reduced hepatic endothelial nitric oxide synthase activity contributes to increased intrahepatic resistance. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, undergoes hepatic metabolism via dimethylarginine-dimethylamino-hydrolase, and is derived by the action of protein-arginine-methyltransferases. Our study assessed whether ADMA, and its stereo-isomer symmetric dimethylarginine (SDMA), are increased in alcoholic hepatitis patients, and determined any relationship with severity of portal hypertension (hepatic venous pressure gradient measurement) and outcome. Fifty-two patients with decompensated alcoholic cirrhosis were studied, 27 with acute alcoholic hepatitis and cirrhosis, in whom hepatic venous pressure gradient was higher (P = 0.001) than cirrhosis alone, and correlated with ADMA measurement. Plasma ADMA and SDMA were significantly higher in alcoholic hepatitis patients and in nonsurvivors. Dimethylarginine-dimethylamino-hydrolase protein expression was reduced and protein-arginine-methyltransferase-1 increased in alcoholic hepatitis livers. ADMA, SDMA and their combined sum, which we termed a dimethylarginine score, were better predictors of outcome compared with Pugh score, MELD and Maddrey's discriminant-function. Alcoholic hepatitis patients have higher portal pressures associated with increased ADMA, which may result from both decreased breakdown (decreased hepatic dimethylarginine-dimethylamino-hydrolase) and/or increased production. Elevated dimethylarginines may serve as important biological markers of deleterious outcome in alcoholic hepatitis.

Effect of parenteral amino acid supplementation on short-term and long-term outcomes in severe alcoholic hepatitis: A randomized controlled trial

Effect of parenteral amino acid supplementation on short-term and long-term outcomes in severe alcoholic hepatitis: A randomized controlled trial

Effect of parenteral amino acid supplementation on short-term and long-term outcomes in severe alcoholic hepatitis: A randomized controlled trial

The effect of parenteral amino acid administration on nutritional state, liver function and mortality was assessed in patients with severe alcoholic hepatitis. Twenty-eight patients received 2 l/day of a solution of dextrose (65 gm/L) and amino acids (25.8 gm/L) for 1 mo, whereas 26 received only the dextrose solution. All patients were allowed to eat a standard hospital diet. During the month in the hospital, there were six deaths in the treatment group and five deaths in the control group. Nitrogen balance improved in the treated group, but not in the control group. Creatinine-height index, triceps skin fold measurement and levels of serum albumin and prealbumin increased similarly in both groups. Serum retinol binding protein increased more in the treatment group than it did in the control group, and transferrin was increased only in the treatment group. Serum bilirubin, type III amino-terminal procollagen peptide and aminopyrine clearance improved more in the treatment group than in the control group, whereas serum AST and prothrombin time improved in the treatment group but not in the control group. Cumulative 2-yr survival rates from the day of entry into the study were 42% and 38% in the treatment and control groups, respectively. Patients who survived 2 yr and patients in the treatment group who died during the 2-yr follow-up had continued improvement in serum retinol binding protein, transferrin, bilirubin and prothrombin time. These parameters were unchanged in patients in the control group who died during follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)