Update on Alcoholic Liver Disease

Educational Objectives

The goal of this program is to improve treatment of acute alcoholic hepatitis (AAH). After hearing and assimilating this program, the clinician will be better able to:

1. Optimize use of the Model for End-stage Liver Disease to determine eligibility for initiation of corticosteroid therapy in the treatment of severe AAH.
2. Identify subgroups of patients with severe AAH who may benefit from liver transplantation.

Summary

Epidemiology: alcohol remains the leading cause of cirrhosis globally (≈60%); ≈35% of patients with alcohol use disorder (AUD) develop alcohol-related liver disease (ARLD); alcohol-related mortality increased in 2020 and remains elevated; there has been an increase in liver transplantations (LT) for patients with ARLD

Disease progression: ≈90% of patients develop some degree of liver steatosis after 2 wk of alcohol consumption (>60 g of alcohol per day); ≤40% develop fibrosis, which may progress to cirrhosis, decompensation, or hepatocellular carcinoma; the risk for acute alcoholic hepatitis (AAH) increases with each increasing stage from steatosis to cirrhosis; each episode of AAH further accelerates the progression to cirrhosis; the patients who require admission to the hospital for AAH management carry a 90-day mortality rate of 20% to 50%

Diagnosing AAH: clinical criteria — acute onset of jaundice within 8 wk prior to presentation; ongoing consumption of >40 g or 60 g alcohol per day (3-4 drinks for women and men) for >6 mo; the last drink was <60 days prior to presentation; aspartate transaminase (AST) greater than alanine transaminase (ALT) with a ratio of 1.5; the value of both liver enzymes should not be >400 IU/L; bilirubin of >3 mg/dL

Potential confounding factors: patients with gastrointestinal bleeding, shock, in the intensive care unit (ICU) on vasopressors, with polysubstance use, or reported history of cocaine use may have ischemic hepatitis contributing to elevated enzymes; a thorough history of medications and herbal supplements should be obtained on admission; reported alcohol use can sometimes be unreliable; pathology testing can help confirm diagnosis; other etiologies, eg, autoimmune disease should be evaluated; though most patients are diagnosed clinically on admission, liver biopsy may be required for a definitive diagnosis at times

Pathogenesis of AAH: altered gut permeability leads to translocation of gut bacteria, lipopolysaccharide, pathogen-associated molecular patterns, and damage-associated molecular patterns into the systemic circulation; these activate the inflammatory cascades in the liver, resulting in the sudden onset of severe inflammation; alcohol also exerts a direct hepatotoxic effect

Potential targets for drugs: drugs targeting gut-liver axis — antibiotics, probiotics, bovine colostrum, and fecal microbiota transplantation (FMT); anti-inflammatory drugs — eg, anakinra; antioxidants — N-acetylcysteine (NAC) has been included in the current guidelines; others — drugs targeting liver regeneration and apoptosis are being investigated

Nutrition: in AAH, the survival benefits of nutrition are more long-term; the current recommendations are to initiate enteral nutrition as soon as possible; feeding tube is safe to use; one should aim for a protein intake of 1.2 to 1.5 g/kg per day (even for patients with cirrhosis); enteral nutritional support should be encouraged in patients who are unable to meet their caloric targets

Corticosteroids: these remain the mainstay of treatment; the STOPAH trial (Thursz et al [2015]) — evaluated prednisolone vs pentoxifylline for severe AAH; prednisolone was associated with an improvement in 28 day survival that did not reach statistical significance and with no improvement in outcomes at 90 days or 1 yr; thus, the benefit of corticosteroids is primarily observed in the short term, ie, within the first 28 days following presentation; there was an increased risk for infection in prednisolone exposed group (13% vs 7%)

Key point: for the majority of patients, corticosteroids should not be initiated on day 1 of hospital admission; infection and other factors should be evaluated and ruled out before corticosteroid initiation

Adding NAC to corticosteroid therapy: Nguyen-Khac et al (2011) — although, with prednisolone plus NAC, 6 mo survival (the primary outcome) was not improved among patients with severe AAH, mortality was significantly lower at 1 mo (8% vs 24%); death because of the hepatorenal syndrome (HRS) and the risk for infection were reduced with the addition of NAC; thus, instead of using corticosteroid therapy alone, addition of NAC into the treatment algorithm can be considered, especially in individuals with an elevated risk for infection

Current treatment algorithm: in patients with suspected AAH, one should treat liver-related complications (eg, volume overload, bleeding, or encephalopathy), provide nutritional support, and rule out infections; managing the underlying AUD is essential; the Model for End-stage Liver Disease (MELD) score can be used to determine severity of AAH; prednisolone 40 mg/day is initiated (in the absence of contraindications) if the MELD score is >20 (severe AAH); Lille score on day 4 or 7 can be used to determine the response; if the Lille score is >0.45 (indicating non-response), prednisolone is stopped and alternative therapies or LT are considered; the American College of Gastroenterology guidelines for ARLD also recommend using the MELD score to determine the severity at presentation, corticosteroids (if indicated), and consideration of NAC; LT is recommended for patients with a MELD score of >50

LT for severe AAH: the prior 6-mo sobriety requirement for LT has shifted a lot over the past several years; Mathurin et al (2011) — the patients with severe AAH who underwent LT had a good 6-mo survival of 77% (vs 23% on standard medical therapy); the patients who benefit from LT are those who do not respond to medical therapy; patients who respond to medical therapy or those who improve with abstinence do not benefit from LT; thus, reassessing patients for response to medical therapy is essential

The ACCELERATE-AH study (Lee et al [2018]): in the retrospective analysis of 147 patients who underwent LT for severe AAH, 94% patients survived for 1 yr and 84% for 3 yr; sustained alcohol use after LT increased the risk for death (by 4-fold); in the early period after transplant, most deaths were from infection or sepsis; predictors of death — high alcohol consumption before LT (>10 drinks per day), any alcohol use after LT, and sustained alcohol use post-transplant; younger age was associated with a higher risk for post-transplant recidivism

Anakinra: the binding of interleukin (IL)-1β to the IL-1 receptor activates the inflammatory cascades that upregulate other cytokines, sensitize hepatocytes to cell death, impair liver regeneration, and promote fibrosis; anakinra is a competitive IL-1 receptor antagonist that prevents the activation of the cascade

Szabo et al (2022): they compared methylprednisolone (28 days) vs triple therapy, ie, anakinra (14 days) plus pentoxifylline (28 days) and zinc (6 mo); though a slight trend towards improvement in overall survival with anakinra was noted, the study was underpowered; there were more fungal infections in the prednisolone group (no infections in the anakinra group)

Gawrieh et al (2024): patients treated with prednisone (using the day-7 Lille score as stopping rule) had better outcomes, ie, better overall survival and higher 90-day survival (90%), when compared with the anakinra group; there was no difference in infections between the 2 groups

FMT in patients with AAH who are corticosteroid ineligible: Pande et al (2023) — FMT was delivered through a naso-duodenal tube, daily for 7 days in patients; the FMT group had a significantly higher survival at 90 days compared with the standard medical therapy (73% vs 40%); although there was no statistical benefit at 28 days, a significant survival benefit was observed at 180 days; a reduction in the incidence of hepatic encephalopathy and recidivism and an improvement in the alcohol craving scores was noted with FMT; thus, FMT is safe but requires additional investigation for true benefit

Emerging therapies: several treatment agents for AAH are currently under investigation, eg, bovine colostrum (to improve gut barrier), emricasan (oral pan-caspase inhibitor), IL-22 fusion protein (antioxidant and antiapoptotic effects), and larsucosterol (functions through epigenetic modulations)

Readings

Arab JP, Díaz LA, Baeza N, et al. Identification of optimal therapeutic window for steroid use in severe alcohol-associated hepatitis: a worldwide study. J Hepatol. 2021;75(5):1026-1033. doi:10.1016/j.jhep.2021.06.019; Gawrieh S, Dasarathy S, Tu W, et al. Randomized trial of anakinra plus zinc vs prednisone for severe alcohol-associated hepatitis. J Hepatol. 2024;80(5):684-693. doi:10.1016/j.jhep.2024.01.031; Lee BP, Mehta N, Platt L, et al. Outcomes of Early Liver Transplantation for Patients With Severe Alcoholic Hepatitis. Gastroenterology. 2018;155(2):422-430.e1. doi:10.1053/j.gastro.2018.04.009; Mathurin P, Moreno C, Samuel D, et al. Early liver transplantation for severe alcoholic hepatitis. N Engl J Med. 2011;365(19):1790-1800. doi:10.1056/NEJMoa1105703; Nguyen-Khac E, Thevenot T, Piquet MA, et al. Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis. N Engl J Med. 2011;365(19):1781-1789. doi:10.1056/NEJMoa1101214; Pande A, Sharma S, Khillan V, et al. Fecal microbiota transplantation compared with prednisolone in severe alcoholic hepatitis patients: a randomized trial. Hepatol Int. 2023;17(1):249-261. doi:10.1007/s12072-022-10438-0; Szabo G, Mitchell M, McClain CJ, et al. IL-1 receptor antagonist plus pentoxifylline and zinc for severe alcohol-associated hepatitis. Hepatology. 2022;76(4):1058-1068. doi:10.1002/hep.32478; Thursz MR, Richardson P, Allison M, et al. Prednisolone or pentoxifylline for alcoholic hepatitis. N Engl J Med. 2015;372(17):1619-1628. doi:10.1056/NEJMoa1412278.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Lee was recorded at the 39th Annual New Treatments in Chronic Liver Disease, held March 15-16, 2025, in Coronado, CA, and presented by Scripps Conference Services and CME. For information on upcoming CME activities from this presenter, please visit Scripps.org. Audio Digest thanks the speakers and Scripps Conference Services and CME for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

Lecture ID:

GE391302

Qualifies for:

ABIM MOC

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.