Maddrey's Discriminant Function Research Articles

3PM-guided innovation in treatments of severe alcohol-associated hepatitis utilizing fecal microbiota transplantation

Abstract Rationale Severe alcohol-associated hepatitis (SAH) is the most critical, acute, inflammatory phenotype within the alcohol-associated liver disease (ALD) spectrum, characterized by high 30- and 90-day mortality. Since several decades, corticosteroids (CS) are the only approved pharmacotherapy offering highly limited survival benefits. Contextually, there is an evident demand for 3PM innovation in the area meeting patients’ needs and improving individual outcomes. Fecal microbiota transplantation (FMT) has emerged as one of the new potential therapeutic options. In this study, we aimed to address the crucial 3PM domains in order to assess (i) the impact of FMT on mortality in SAH patients beyond CS, (ii) to identify factors associated with the outcome to be improved (iii) the prediction of futility, (iv) prevention of suboptimal individual outcomes linked to increased mortality, and (v) personalized allocation of therapy. Methods We conducted a prospective study (NCT04758806) in adult patients with SAH who were non-responders (NR) to or non-eligible (NE) for CS between January 2018 and August 2022. The intervention consisted of five 100 ml of FMT, prepared from 30 g stool from an unrelated healthy donor and frozen at − 80 °C, administered daily to the upper gastrointestinal (GI) tract. We evaluated the impact of FMT on 30- and 90-day mortality which we compared to the control group selected by the propensity score matching and treated by the standard of care; the control group was derived from the RH7 registry of patients hospitalized at the liver unit (NCT04767945). We have also scrutinized the FMT outcome against established and potential prognostic factors for SAH — such as the model for end-stage liver disease (MELD), Maddrey Discriminant Function (MDF), acute-on-chronic liver failure (ACLF), Liver Frailty Index (LFI), hepatic venous-portal pressure gradient (HVPG) and Alcoholic Hepatitis Histologic Score (AHHS) — to see if the 3PM method assigns them a new dimension in predicting response to therapy, prevention of suboptimal individual outcomes, and personalized patient management. Results We enrolled 44 patients with SAH (NR or NE) on an intention-to-treat basis; we analyzed 33 patients per protocol for associated factors (after an additional 11 being excluded for receiving less than 5 doses of FMT), and 31 patients by propensity score matching for corresponding individual outcomes, respectively. The mean age was 49.6 years, 11 patients (33.3%) were females. The median MELD score was 29, and ACLF of any degree had 27 patients (81.8%). FMT improved 30-day mortality (p = 0.0204) and non-significantly improved 90-day mortality (p = 0.4386). Univariate analysis identified MELD ≥ 30, MDF ≥ 90, and ACLF grade > 1 as significant predictors of 30-day mortality, (p = 0.031; p = 0.014; p = 0.034). Survival was not associated with baseline LFI, HVPG, or AHHS. Conclusions and recommendations in the framework of 3PM In the most difficult-to-treat sub-cohort of patients with SAH (i.e., NR/NE), FMT improved 30-day mortality. Factors associated with benefit included MELD ≤ 30, MDF ≤ 90, and ACLF < 2. These results support the potential of gut microbiome as a therapeutic target in the context of 3PM research and vice versa — to use 3PM methodology as the expedient unifying template for microbiome research. The results allow for immediate impact on the innovative concepts of (i) personalized phenotyping and stratification of the disease for the clinical research and practice, (ii) multilevel predictive diagnosis related to personalized/precise treatment allocation including evidence-based (ii) prevention of futile and sub-optimally effective therapy, as well as (iii) targeted prevention of poor individual outcomes in patients with SAH. Moreover, our results add to the existing evidence with the potential to generate new research along the SAH’s pathogenetic pathways such as diverse individual susceptibility to alcohol toxicity, host-specific mitochondrial function and systemic inflammation, and the role of gut dysbiosis thereof.

15-Year Long-Term Follow-Up on the Progression to Liver Cancer in a Patient with Alcoholic Hepatitis Who Continued Drinking: A Case Report and Clinical Approach

Objectives: This case report aims to present the long-term clinical progression of a patient diagnosed with alcoholic hepatitis, which subsequently advanced to liver cirrhosis and hepatocellular carcinoma over a 15-year period. The report highlights the impact of continued alcohol consumption on the progression of alcoholic liver disease and provides a clinical analysis of the course of the disease.Methods: A single patient diagnosed with alcoholic hepatitis was analyzed retrospectively. The patient was treated with both traditional Korean medicine and conventional medicine over multiple hospitalizations between 2012 and 2021. Clinical outcomes were monitored through blood chemistry, imaging studies, and Child-Pugh scores.Results: Despite consistent treatment, the patient’s continued alcohol consumption accelerated the progression from alcoholic hepatitis to cirrhosis and, eventually, hepatocellular carcinoma. The patient’s condition remained classified as Child-Pugh B throughout the follow-up, and he ultimately expired in 2023.Conclusion: This case emphasizes that alcohol cessation is crucial in preventing the rapid progression from alcoholic hepatitis to liver cancer. Early detection through noninvasive fibrosis tests such as FibroScan, proactive management of complications, and the use of prognostic tools such as Maddrey Discriminant function (MDF), in addition to patient education, are essential for better outcomes.

Severe Alcoholic Hepatitis-optimizing Medical Management: Whether we need a Liver Transplant

Severe alcoholic hepatitis is an ethical and clinical conundrum, wherein a liver transplant is often recommended. The adequacy of medical treatment versus the risk of recidivism after transplant is often debated. Complete recovery in 26 of 27 patients with severe alcoholic hepatitis was observed, and hence the data was retrospectively analysed. Methods: 27 patients, with severe alcoholic hepatitis, with Maddrey's discriminant function between 59.7 to 165.2 (mean 107.53), from June 2017 to May 2022, were followed up for between 11 months to 6 years. INR ranged from 1.99 to 3.7 (mean 2.709), and bilirubin was between 7.6 to 37.01, (mean 20.859). 8 patients had pre-existing liver cirrhosis. All patients received probiotics, nutritional support, physical rehabilitation, saturated fat (clarified butter/ desi ghee) supplementation, and anti-oxidant support. At 90 days, total bilirubin improved to between 1.0 to 6.8 (mean 2.625). ALT (Alanine Transaminase/ SGPT) ranged from 65 to 550 (mean ALT – 197); and AST (Aspartate Transaminase / SGOT) ranged from 58 to 810 (mean AST – 271.51). Both the AST and ALT were near normal after 90 days. One patient died due to bacterial pneumonia and sepsis; the remaining 26 patients made a complete recovery. All patients including those with diagnosed liver cirrhosis, had complete resolution of their ascites, and near-normal liver function. At the last outpatient visit, none had ascites, edema, or encephalopathy, and had normal albumin levels and INR values. Conclusion: Probiotics, nutrition, a saturated fat diet, and exercise; all have shown benefits in patients with severe alcoholic hepatitis when tested individually. Concomitant use of all the above has not been reported in the treatment of alcoholic hepatitis. The role of nutrition alone versus the contribution of nutritional deficiencies and the role of gut-derived endotoxemia need to be studied in detail. How to identify patients who need a transplant, if it is needed at all, remains a challenge.

An artificial intelligence-generated model predicts 90-day survival in alcohol-associated hepatitis: A global cohort study.

Alcohol-associated hepatitis (AH) poses significant short-term mortality. Existing prognostic models lack precision for 90-day mortality. Utilizing artificial intelligence in a global cohort, we sought to derive and validate an enhanced prognostic model. The Global AlcHep initiative, a retrospective study across 23 centers in 12 countries, enrolled patients with AH per National Institute for Alcohol Abuse and Alcoholism criteria. Centers were partitioned into derivation (11 centers, 860 patients) and validation cohorts (12 centers, 859 patients). Focusing on 30 and 90-day postadmission mortality, 3 artificial intelligence algorithms (Random Forest, Gradient Boosting Machines, and eXtreme Gradient Boosting) informed an ensemble model, subsequently refined through Bayesian updating, integrating the derivation cohort's average 90-day mortality with each center's approximate mortality rate to produce posttest probabilities. The ALCoholic Hepatitis Artificial INtelligence Ensemble score integrated age, gender, cirrhosis, and 9 laboratory values, with center-specific mortality rates. Mortality was 18.7% (30d) and 27.9% (90d) in the derivation cohort versus 21.7% and 32.5% in the validation cohort. Validation cohort 30 and 90-day AUCs were 0.811 (0.779-0.844) and 0.799 (0.769-0.830), significantly surpassing legacy models like Maddrey's Discriminant Function, Model for End-Stage Liver Disease variations, age-serum bilirubin-international normalized ratio-serum Creatinine score, Glasgow, and modified Glasgow Scores ( p < 0.001). ALCoholic Hepatitis Artificial INtelligence Ensemble score also showcased superior calibration against MELD and its variants. Steroid use improved 30-day survival for those with an ALCoholic Hepatitis Artificial INtelligence Ensemble score > 0.20 in both derivation and validation cohorts. Harnessing artificial intelligence within a global consortium, we pioneered a scoring system excelling over traditional models for 30 and 90-day AH mortality predictions. Beneficial for clinical trials, steroid therapy, and transplant indications, it's accessible at: https://aihepatology.shinyapps.io/ALCHAIN/ .

Human Neutrophil Alpha-Defensins Promote NETosis and Liver Injury in Alcohol-Related Liver Cirrhosis: Potential Therapeutic Agents.

Background: Neutrophils are thought to play a pivotal role in the pathogenesis of many inflammatory diseases, such as hepatitis, liver cirrhosis, etc. Activated human neutrophils release human neutrophil peptides (HNP1-3) or alpha-defensins that are antimicrobial peptides in azurophil granules. Furthermore, HNP1-3 build a scaffold of neutrophil extracellular traps (NETs) and promote the process of programmed cell death called NETosis. Our study aimed to investigate the role of alpha-defensins in the pathogenesis of alcohol-related liver cirrhosis (ALC). Methods: The concentrations of alpha-defensins in the plasma of 62 patients with ALC and 24 healthy subjects were measured by ELISA. The patients with ALC were prospectively recruited based on the severity of liver dysfunction according to the Child-Pugh and Model of End-Stage Liver Disease-Natrium (MELD-Na) scores, modified Maddrey's Discriminant Function (mDF), and the presence of ALC complications. Results: The concentrations of alpha-defensins in plasma were significantly higher in the ALC patients than in the controls. The plasma levels of HNP1-3 correlated with the MELD and mDF scores. ALC subgroups with MELD > 20 and mDF > 32 displayed significantly higher HNP1-3 concentrations. The plasma levels of HNP1-3 revealed a good predictive AUC for hepatic encephalopathy and ascites development (0.81 and 0.74, respectively) and for patient survival (0.87) in those over 40 years of age. Conclusion: These findings suggest that alpha-defensins play an important role in the assessment of ALC.

Granulocyte-monocyte/macrophage apheresis for steroid-nonresponsive or steroid-intolerant severe alcohol-associated hepatitis: A pilot study.

Patients with severe alcohol-associated hepatitis (SAH) have a high short-term mortality rate. Unmet needs exist in patients who are refractory to corticosteroids (CS) or are ineligible for early liver transplantation. This was a prospective, open-label, nonrandomized pilot study conducted at a liver transplant center in Tokyo, Japan, starting in October 2015. Lille model and Model for End-stage Liver Disease (MELD) score-defined CS nonresponsive or CS-intolerant patients with SAH who fulfilled the inclusion criteria (leukocytosis over 10,000/μL, etc.) were considered for enrollment. The median duration from admission to enrollment was 23 days (IQR, 14-31 days), after standard of care. Granulocyte-monocyte/macrophage apheresis (GMA) performed with Adacolumn twice per week, up to 10 times per treatment course, was evaluated. 13 GMA treatments were conducted through December 2021. Maddrey Discriminant Function was 53.217.7 at admission. The overall survival rate was 90.9% at 90 and 180 days. MELD scores significantly improved, from median (IQRs) of 23 (20-25) to 15 (13-21) after GMA (p<0.0001). Estimated mortality risks using the Lille model and MELD scores significantly improved from 20.9%±16.5% to 7.4%±7.3% at 2 months and from 30.4%±21.3% to 11.6%±10.8% at 6 months, respectively (both p<0.01), and were internally validated. The cumulative rate of alcohol relapse was 35.9% per year. No severe adverse events were observed. In exploratory analysis, granulocyte colony-stimulating factor levels were significantly correlated with prognostic systems such as MELD-Sodium scores after GMA (correlation coefficient= -0.9943, p<0.0001) but not before GMA (p=0.62). Compared to published studies, GMA is associated with a lower-than-expected 90- and 180-day mortality in patients with CS-nonresponsive or CS-intolerant SAH. GMA may meet the needs as a salvage anti-inflammatory therapy for SAH. (Trial registration: UMIN000019351 and jRCTs No.032180221) (274 words).

Prothrombin time predicts steroid response in severe alcohol-related hepatitis.

Alcohol-related hepatitis (AH) is the most severe form of acute alcohol-related liver disease. Maddrey's discriminant function ≥32 defines the severe form of AH, which is associated with a high mortality. Steroid therapy represents the main medical treatment that may reduce short-term mortality. Lille score at day 7 assesses the therapeutic response to steroid therapy. At present, no parameters able to predict the response to steroid therapy have been highlighted. The aim of the present study was to evaluate if baseline prothrombin time (BPT) could predict the response to steroid in severe AH (sAH). Patients consecutively admitted in two Italian Liver Units, from 2017 to 2022, suffering from sAH were included. Data were collected prospectively. In order to evaluate if BPT could predict steroid response, we assessed the correlation between BPT using the Lille score at day 7. A total of 52 patients received steroid treatment were enrolled in the study. The response to therapy was assessed by Lille score at day 7. Responders were 34 patients (65%), non-responders 18 patients (34%). BPT significantly predicted the steroid response (p < .001). The likelihood of not responding to the steroid therapy was significantly higher in patients with higher BPT (OR = 2.954). BPT value predicted steroid response in patients with sAH. BPT could quickly identify non-responder patients to steroid therapy, reducing the risk of infections and it could allow the early evaluation for liver transplantation.

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.

New prognostic model for hospitalized patients with alcoholic cirrhosis and Maddrey's discriminant function

Few studies have investigated the prognosis of patients with non-severe alcoholic hepatitis (Non-SAH). The study aimed to develop a new prognostic model for patients with especially Non-SAH. We extracted 316 hospitalized patients with alcoholic cirrhosis without severe alcoholic hepatitis, defined as Maddrey's discriminant function score lower than 32, from the retrospective Korean Acute-on-Chronic Liver Failure (KACLiF) cohort to develop a new prognostic model (training set), and validated it in 419 patients from the prospective KACLiF cohort (validation set). Prognostic factors for death and liver transplantation were analyzed to construct a prognostic model. Twenty-one and 24 patients died within 6 months in both sets, respectively. In the training set, the highest area under the curve (AUC) of conventional prognostic models was 0.765, 0.732, and 0.684 for 1-, 3-, and 6-month mortality, respectively. Refractory ascites, vasopressor use, and hyponatremia were independently associated with mortality of cirrhotic patients with Non-SAH. The new model consisted of four variables: past deterioration, neutrophil proportion > 70%, Na < 128 mmol/L, and vasopressor use. It showed the highest accuracy for short-term mortality in the training and validation sets (0.803 and 0.786; 0.797 and 0.776; and 0.789 and 0.721 for 1-, 3-, and 6-month mortality, respectively). There is a group of patients with high risk among those classified as Non-SAH. The new model will help stratifying cirrhotic patients with Non-SAH more accurately in terms of prognosis. The patients with high Non-SAH score need to monitor closely and might be considered for preemptive liver transplantation. ClinicalTrials.gov identifier: NCT02650011.

The Model for End-stage Liver Disease 3.0 is not superior to the Model for End-stage Liver Disease-Na in predicting survival: A retrospective cohort study.

The Model for End-stage Liver Disease (MELD) 3.0 yields high prognostic performance for patients with end-stage liver disease (ESLD). However, its prognostic performance for patients with alcohol-related liver disease (ARLD) has limited results. The aim of this study was to perform such an evaluation among Chinese patients. Patients hospitalized with ARLD in one institution between 2015 and 2018 were retrospectively included and followed up for 12 months. The original MELD, MELD-Na, MELD 3.0, and modified Maddrey discriminant function (MDF) scores were calculated for each patient at baseline. Their prognostic performances for 1-year survival were assessed. Time-dependent receiver operating characteristic curves were constructed, and AUCs were calculated for each scoring system. Among the 576 patients included in our analysis, 209 patients had alcoholic hepatitis (AH). By the 1-year follow-up, 14.8% (84/567) of all the patients and 23.4% (49/209) of those with AH had died. Overall, patients who had died had higher MELD, MELD-Na, MELD 3.0, and MDF scores (all p < 0.001) than those who had not. The same was true in the AH subgroup (MELD: p < 0.001, MELD-Na: p < 0.001, MELD 3.0: p = 0.007, MDF: p = 0.017). The AUC of the MELD 3.0 for prediction of 1-year survival among patients with ARLD was 0.682, lower than that of the original MELD (0.728, p < 0.001) and MELD-Na (0.735, p < 0.001). Moreover, in the AH subgroup, the AUC for the prediction of 1-year survival was lower than that in the MELD-Na subgroup (0.634 vs. 0.708, p < 0.001). The MELD 3.0 was not superior to the original MELD or the MELD-Na in predicting the mortality of patients with ARLD.

Prognostic and diagnostic scoring models in acute alcohol-associated hepatitis: A review comparing the performance of different scoring systems.

Alcohol-associated hepatitis (AAH) is a severe form of liver disease caused by alcohol consumption. In the absence of confounding factors, clinical features and laboratory markers are sufficient to diagnose AAH, rule out alternative causes of liver injury and assess disease severity. Due to the elevated mortality of AAH, assessing the prognosis is a radical step in management. The Maddrey discriminant function (MDF) is the first established clinical prognostic score for AAH and was commonly used in the earliest AAH clinical trials. A MDF > 32 indicates a poor prognosis and a potential benefit of initiating corticosteroids. The model for end stage liver disease (MELD) score has been studied for AAH prognostication and new evidence suggests MELD may predict mortality more accurately than MDF. The Lille score is usually combined to MDF or MELD score after corticosteroid initiation and offers the advantage of assessing response to treatment a 4-7 d into the course. Other commonly used scores include the Glasgow Alcoholic Hepatitis Score and the Age Bilirubin international normalized ratio Creatinine model. Clinical AAH correlate adequately with histologic severity scores and leave little indication for liver biopsy in assessing AAH prognosis. AAH presenting as acute on chronic liver failure (ACLF) is so far prognosticated with ACLF-specific scoring systems. New artificial intelligence-generated prognostic models have emerged and are being studied for use in AAH. Acute kidney injury (AKI) is one possible complication of AAH and is significantly associated with increased AAH mortality. Predicting AKI and alcohol relapse are important steps in the management of AAH. The aim of this review is to discuss the performance and limitations of different scoring models for AAH mortality, emphasize the most useful tools in prognostication and review predictors of recurrence.

MELD 3.0 adequately predicts mortality and renal replacement therapy requirements in patients with alcohol-associated hepatitis

Model for End-Stage Liver Disease (MELD) score better predicts mortality in alcohol-associated hepatitis (AH) but could underestimate severity in women and malnourished patients. Using a global cohort, we assessed the ability of the MELD 3.0 score to predict short-term mortality in AH. This was a retrospective cohort study of patients admitted to hospital with AH from 2009 to 2019. The main outcome was all-cause 30-day mortality. We compared the AUC using DeLong's method and also performed a time-dependent AUC with competing risks analysis. A total of 2,124 patients were included from 28 centres from 10 countries on three continents (median age 47.2 ± 11.2 years, 29.9% women, 71.3% with underlying cirrhosis). The median MELD 3.0 score at admission was 25 (20-33), with an estimated survival of 73.7% at 30 days. The MELD 3.0 score had a better performance in predicting 30-day mortality (AUC:0.761, 95%CI:0.732-0.791) compared with MELD sodium (MELD-Na; AUC: 0.744, 95% CI: 0.713-0.775; p= 0.042) and Maddrey's discriminant function (mDF) (AUC: 0.724, 95% CI: 0.691-0.757; p= 0.013). However, MELD 3.0 did not perform better than traditional MELD (AUC: 0.753, 95% CI: 0.723-0.783; p= 0.300) and Age-Bilirubin-International Normalised Ratio-Creatinine (ABIC) (AUC:0.757, 95% CI: 0.727-0.788; p= 0.765). These results were consistent in competing-risk analysis, where MELD 3.0 (AUC: 0.757, 95% CI: 0.724-0.790) predicted better 30-day mortality compared with MELD-Na (AUC: 0.739, 95% CI: 0.708-0.770; p= 0.028) and mDF (AUC:0.717, 95% CI: 0.687-0.748; p= 0.042). The MELD 3.0 score was significantly better in predicting renal replacement therapy requirements during admission compared with the other scores (AUC: 0.844, 95% CI: 0.805-0.883). MELD 3.0 demonstrated better performance compared with MELD-Na and mDF in predicting 30-day and 90-day mortality, and was the best predictor of renal replacement therapy requirements during admission for AH. However, further prospective studies are needed to validate its extensive use in AH. Severe AH has high short-term mortality. The establishment of treatments and liver transplantation depends on mortality prediction. We evaluated the performance of the new MELD 3.0 score to predict short-term mortality in AH in a large global cohort. MELD 3.0 performed better in predicting 30- and 90-day mortality compared with MELD-Na and mDF, but was similar to MELD and ABIC scores. MELD 3.0 was the best predictor of renal replacement therapy requirements. Thus, further prospective studies are needed to support the wide use of MELD 3.0 in AH.

A257 ASSOCIATION OF DIETITIAN CONSULTATION WITH INFECTION RATES IN PATIENTS WITH SEVERE ALCOHOLIC HEPATITIS

Abstract Background Patients with alcoholic hepatitis have significant morbidity and mortality, frequently infection related. They are often malnourished from increased nutritional demands. Studies show conflicting results on whether nutritional therapy reduces infections. Purpose To examine if dietitian consultation is associated with lower infection rates in patients with alcoholic hepatitis. Method Retrospective chart review of adults aged 18-75 admitted to The Ottawa Hospital for severe alcoholic hepatitis between January 1, 2016 and December 31, 2018. Patients with co-existing liver diseases were excluded. Descriptive statistics compared those with and without dietitian consultation during admission. The primary exposure was dietitian consultation over 48 hours before infection. The primary outcome was infection over 48 hours after admission. Result(s) 64 patients were assessed (mean age 52.3+/-10.9 years; mean Maddrey Discriminant Function 53.6+/-33.2). Those with dietitian consultation (N=17, 26.6%) had greater Charlson (p=0.016) and Model for End Stage Liver Disease (p=0.048) scores, with no difference in steroid use (p=0.60). Among 53 patients without infection on admission, 10 had infection in hospital, of whom 4 had dietitian consultation before infection. Dietitian consultation was associated with increased infection risk (OR 6.5, 95%CI=1.3-33.2). Conclusion(s) Only the sickest patients received dietitian consultation, which likely explains the observed increased infection risk. Given high malnutrition rates in this population, our results suggest a significant care gap. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest None Declared

Correlation Between Computed Tomography Findings and the Laboratory Test-Derived Severity Score in Patients With Severe Acute Alcoholic Hepatitis.

This study aimed to compare computed tomography (CT) findings between patients with severe and nonsevere acute alcoholic hepatitis (AAH). We included 96 patients diagnosed with AAH between January 2011 and October 2021 who underwent 4-phase liver CT and laboratory blood tests. Two radiologists reviewed the initial CT images with respect to distribution and grade of hepatic steatosis; transient parenchymal arterial enhancement (TPAE); and presence of cirrhosis, ascites, and hepatosplenomegaly. A Maddrey discriminant function score (4.6 × [patient's prothrombin time - control] + total bilirubin [mg/mL]) was used as cutoff indicator for severity, with a score of 32 or higher indicating severe disease. The image findings were compared between the severe (n = 24) and nonsevere (n = 72) groups using the χ 2 test or Fisher exact test. After univariate analysis, the most significant factor was identified using a logistic regression analysis. In the univariate analysis, there were significant between-group differences in the TPAE, liver cirrhosis, splenomegaly, and ascites ( P < 0.0001, P < 0.0001, P = 0.0002, and P = 0.0163, respectively). Among them, TPAE was the only significant factor for severe AAH ( P < 0.0001; odds ratio, 48.1; 95% confidence interval, 8.3-280.6). Using this single indicator, the estimated accuracy, positive predictive, and negative predictive values were 86%, 67%, and 97%, respectively. Transient parenchymal arterial enhancement was the only significant CT finding in severe AAH.

Design of a multicenter randomized clinical trial for treatment of Alcohol-Associated Hepatitis

BackgroundMortality is high for severe alcohol-associated hepatitis (AH). Corticosteroids are the standard of care for patients without contraindications. Recent data showed that interleukin-1β receptor antagonist anakinra attenuated inflammation and liver damage. We designed a multicenter, double-blind, randomized controlled trial to assess the safety and efficacy of anakinra compared to prednisone. MethodsPatients meeting the clinical and biochemical criteria for severe AH with MELD scores between 20 and 35 were recruited at eight clinical sites. Eligible patients enrolled in the study were randomized to anakinra, 100 mg subcutaneous injection for 14 days, plus zinc sulfate 220 mg for 90 days, vs. prednisone 40 mg PO daily for 30 days. Matching placebos for anakinra, zinc, and prednisone were provided to mask the treatment. Participants were followed for 180 days. The primary outcome was overall survival at 90 days. An unadjusted log-rank test was used to compare the survival of the two treatments in the first 90 days. Between July 10, 2020, and March 4, 2022, we screened 1082 patients with severe AH, and 147 eligible patients were enrolled and randomized. The average baseline MELD score was 25 [range 20–35], Maddrey discriminant function (MDF) was 59.4 [range 20.2–197.5]. The mean aspartate transaminase (AST)-to-alanine transaminase (ALT) ratio was 3.5. The baseline characteristics were not statistically different between the two treatment groups. ConclusionsThe study provided a direct comparison of the survival benefits and safety profiles of anakinra plus zinc vs. prednisone in patients with severe AH.

Outnumbered: Control Prothrombin Time in Maddrey's Discriminant Function Impacts Steroid Use but Not Mortality in Alcoholic Hepatitis.

In alcoholic hepatitis (AH), increases in the total bilirubin (TB) and the prothrombin time (PT), which are included in the Maddrey's discriminant function (MDF) and the model for end-stage liver disease (MELD), are associated with poor outcomes. However, the impact of which control PT in the MDF to use compared to the MELD on the outcomes in AH is unknown. Our aim is to determine whether the choice of the control PT used in the MDF calculations has any impact on steroid use and survival when compared to the MELD in those with AH. Through retrospective chart review, we analyzed 882 subjects who were admitted from 2012 to 2020 with acute AH. Their MDF was calculated [(TB + 4.6 × (PT-control)] using the following three different control PTs: 12, 13.5, and 14.8 s, and was compared to the MELD. The primary outcomes were steroid use and 30-day survival. When it was stratified by the control PT, the percentage of MDF ≥ 32 (the threshold for steroids) decreased with increasing control PT (70%, 61%, and 52%, respectively), along with decreased steroid use (91%, 84%, and 75%, respectively). Those who received steroids were not shown to have improved 30-day survival compared to those who did not receive steroids (p = 0.41). The ability of the MDF for each control PT threshold to predict 30-day survival was similar (AUROC 0.735), and was lower compared to the MELD (0.767). While the choice of PT control in the MDF impacted the use of steroids in AH, the use of steroids and the choice of PT control used did not impact the overall survival. Regardless of which control PT was used in the MDF, the MELD was better at predicting 30-day survival. Important information: Background: Treatment with steroids is indicated in alcoholic hepatitis (AH) with Maddrey discriminant function (MDF) ≥ 32 and the model for end-stage liver disease (MELD) ≥ 20. The impact that the control prothrombin time (PT) value that is used in MDF has on steroid use and survival in AH is poorly understood. The choice of control PT that is used when calculating the MDF impacts the use of steroids but does not impact mortality. The MELD was better than the MDF at any control PT used in predicting survival in acute AH. Providers should be aware that higher control PT's have an effect on treatment decisions but should not generally impact survival in this population. The MELD appears to better predict 30-day survival in this population.

A phase II, multicenter, open-label, randomized trial of pegfilgrastim for patients with alcohol-associated hepatitis.

SummaryBackgroundIn trials conducted in India, recombinant granulocyte colony stimulating factor (GCSF) improved survival in alcohol-associated hepatitis (AH). The aim of this trial was to determine the safety and efficacy of pegfilgrastim, a long-acting recombinant GCSF, in patients with AH in the United States.MethodsThis prospective, randomized, open label trial conducted between March 2017 and March 2020 randomized patients with a clinical diagnosis of AH and a Maddrey discriminant function score ≥32 to standard of care (SOC) or SOC+pegfilgrastim (0.6 mg subcutaneously) on Day 1 and Day 8 (clinicaltrials.gov NCT02776059). SOC was 28 days of either pentoxifylline or prednisolone, as determined by the patient's primary physician. The second injection of pegfilgrastim was not administered if the white blood cell count exceeded 30,000/mm3 on Day 8. Primary outcome was survival at Day 90. Secondary outcomes included the incidence of acute kidney injury (AKI), hepatorenal syndrome (HRS), hepatic encephalopathy, or infections.FindingsThe study was terminated early due to COVID19 pandemic. Eighteen patients were randomized to SOC and 16 to SOC+pegfilgrastim. All patients received prednisolone as SOC. Nine patients failed to receive a second dose of pegfilgrastin due to WBC > 30,000/mm3 on Day 8. Survival at 90 days was similar in both groups (SOC: 0.83 [95% confidence interval [CI]: 0.57–0.94] vs. pegfilgrastim: 0.73 [95% CI: 0.44–0.89]; p > 0.05; CI for difference: -0.18–0.38). The incidences of AKI, HRS, hepatic encephalopathy, and infections were similar in both treatment arms and there were no serious adverse events attributed to pegfilgrastim.InterpretationThis phase II trial found no survival benefit at 90 days among subjects with AH who received pegfilgrastim+prednisolone compared with subjects receiving prednisolone alone.Fundingwas provided by the United States National Institutes of Health and National Institute on Alcohol Abuse and Alcoholism U01-AA021886 and U01-AA021884.

S1315 Are We Following the Guidelines in the Treatment of Patients With Alcoholic Hepatitis?

Introduction: Alcoholic liver disease is one of the leading causes of chronic liver disease worldwide and accounts for up to 48% of cirrhosis-associated deaths in the United States. Corticosteroids provide a short-term survival benefit in about half of treated patients with Severe Alcoholic Hepatitis. The decision is made on the basis of risk stratification by Maddrey or Meld scoring system. We hope to assess how well we are at identifying and treating the patient population at Crozer Chester Medical Center Methods: We did a retrospective review of patients admitted to Crozer Chester Medical Center from October 2021 to January 2017. We filtered patients based on ICD-10 codes for Alcoholic Hepatitis. We included the patient 18 years and above hospitalized at Crozer Chester Medical Center with the diagnosis of alcoholic hepatitis. We excluded the patients who had sepsis on admission, had active hepatitis B or C, had acute kidney injury present on admission, had upper gastrointestinal bleed present on admission, patients requiring steroids due to some other condition. Results: We had an initial sample of 431 patients. After clearing duplicates or missing data entries, we were left with 321 patients. After applying the exclusion criteria, we were left with 60 patients, those who did not have any contraindications to steroid use. 90% (N=54) of those patients had no risk calculation score documented. There was no statistically significant difference between the teaching and non-teaching service regarding risk score documentation (p=0.43). We identified 20 patients from the sample who would have benefited from steroids. Out of those, only 47%(N=8) received steroids. Out of those, only 5 (29%) received prednisolone (Figure). Conclusion: Currently, the American College of gastroenterology guideline recommends using steroids in the high-risk patient population. (2)Various risks calculating criteria like Maddrey's Discriminant Function and MELD score have been developed to determine the patients who fulfill the criteria for severe disease and can benefit from a course of steroids Various strategies can be implemented to improve adherence to guidelines. The scoring system should be documented when admitting patients with alcoholic hepatitis Changes in the electronic medical records can be considered as displaying a popup reminder to calculate the appropriate risk score, to consult a specialist, or to automatically calculate the risk score can be made as it would be beneficial in this maintaining adherence to guidelines.Figure 1.: Steroids given to patients with high Maddrey/Meld score with no contraindications

Therapeutic plasma exchange is a safe and effective bridge therapy in patients with alcohol-associated ACLF not having immediate prospects for liver transplantation-A case-control, pilot study.

Therapeutic plasma exchange (TPE) is a well-established treatment modality in acute liver failure patients, but its efficacy in treating acute on chronic liver failure (ACLF) patients is yet to be established. To assess the efficacy and safety of TPE in patients with alcohol-associated ACLF who were nonresponders to standard medical treatment (SMT) and without immediate prospects for liver transplantation. Twenty-eight alcohol-related ACLF (grade II) patients (14 cases and 14 controls) were enrolled in the study. Cases underwent standard volume TPE along with SMT while the controls were on SMT alone. The change (baseline to day 10) in laboratory parameters, cytokine concentrations, clinical severity scores along with 30 and 90 day mortality rates were noted and compared between the two groups. The adverse events (AEs) were noted in the groups and analyzed. A total of 51 TPE procedures were performed in 14 patients (average of 3.62 procedures/patient). TPE was effective in reduction of serum bilirubin, ammonia, activated partial thromboplastin time, prothrombin time, international normalized ratio, and severity scores (ACLF Research Consortium, Maddrey's discriminant function, and model for end-stage liver disease) (P < .05). There was no significant difference in the reduction of serum interleukin-6 (IL-6), IL-10, and tumor necrosis factor-α concentrations among cases. Among the cases who received the complete TPE interventions, 30- and 90-day mortality rates were lower in the cases as compared to controls albeit only the 90-day mortality was significantly different. Procedure-related AEs was observed in 2% of procedures. TPE is an effective and well-tolerated bridge therapy in patients with alcohol-associated ACLF of moderate severity not improving on SMT and without immediate prospects for liver transplantation.

IL-1 receptor antagonist plus pentoxifylline and zinc for severe alcohol-associated hepatitis.

Patients with severe alcohol-associated hepatitis (AH) have high mortality. Corticosteroids improve survival only for 30days. We targeted inflammation, cellular injury, and gut leakiness in a randomized clinical trial comparing combination therapy to corticosteroids on 180-day survival. Subjects with a clinical diagnosis of severe AH (Model for End-Stage Liver Disease [MELD] >20, Maddrey discriminant function [MDF] >32) were randomized to receive methylprednisolone (PRED; 28days) or a combination of anakinra (14days) plus pentoxifylline (28days) plus zinc (COMB; 180days). The primary endpoint was survival at 180days. The study was designed in 2013, initiated in October 2014, and completed in March 2018. Five hundred patients were screened to randomize 104subjects with a clinical diagnosis of AH with a MELD score >20. Fifty-three patients were randomized into the COMB and 50 to the PRED treatment; 1 dropped out of the study before randomization. Mean age was 45.3±10.4years; 60.6% were males, 92.3% White, and mean MELD 25.7±3.9. Kaplan-Meier survival estimate at 180 days was 67.9% in COMB and 56% in PRED (HR=0.69; p=0.3001). Survival curves separated by 90days (COMB, 69.8%; PRED, 58.0%; HR=0.69; p=0.28). Survival at 28days was similar between the COMB (83.4%) and PRED groups (81.2%; HR=0.91; p=0.85). There were no unexpected serious adverse events, and incidence of infection was comparable between groups. MELD 20-25 and MELD >26strata showed nonsignificant treatment effects in favor of COMB. A combination of anakinra, pentoxifylline plus zinc provides similar survival benefits compared to corticosteroid therapy in severe AH.