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World Gastroenterology Organisation

Global Guardian of Digestive Health. Serving the World.

 

Alcohol-Associated Hepatitis: Current Guidelines and Promising Emerging Therapies

Vol. 31, Issue 1 (March 2026)

Jonathan Lee, MDJonathan Lee, MD
Resident Physician, Internal Medicine
Rush University Medical Center
Chicago, IL, USA
 

Zoë Post, MD, MScZoë Post, MD, MSc
Fellow Physician, Gastroenterology & Hepatology
Northwestern Medicine
Chicago, IL, USA
 

Nancy Reau, MDNancy Reau, MD
Professor, Department of Internal Medicine, Division of Digestive Diseases and Nutrition
Rush University Medical Center
Chicago, IL, USA

 

Introduction

Alcohol-associated hepatitis (AH) is a subset of alcohol-related liver disease characterized by acute liver inflammation in the setting of significant alcohol use. It is associated with significant morbidity and a 90-day mortality rate ranging as high as 30-50%.1, 2 The clinical manifestations of AH can vary from the rapid onset of jaundice to acute-on-chronic liver failure, particularly in patients with underlying liver pathology or alcohol use disorder (AUD). Female sex, and increased body mass index (BMI) remain the most established risk factors for the development of AH. While heavy alcohol consumption is commonly observed amongst patients who develop AH, the exact thresholds for amount and duration of alcohol use are still unknown. One recent systematic review estimated the prevalence of AH to be approximately 3.5% in unselected populations.3 However, the highest incidence rates in the United States are found amongst individuals aged 40-59, with a startling increase in incidence being observed amongst young adults aged 20-39 years in recent years.4

The diagnosis of AH is based upon clinical history, physical examination, and laboratory evaluation. The most widely accepted diagnostic criteria proposed by a consortium of experts from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) is summarized in Table 1.5

 Table 1. NIAAA diagnostic criteria for AH
Table 1. NIAAA diagnostic criteria for AH

Liver biopsy can further confirm the diagnosis if uncertainty exists. Several scoring systems based upon histological findings have been observed to have prognostic value, with the presence of cirrhosis conferring a worse prognosis.6

Once diagnosed, AH is further classified based on severity and a patient’s likelihood to benefit from pharmacologic therapy. Current guidelines recommend using the well-validated Model for End-Stage Liver Disease (MELD) or Maddrey discrimination function (DF) scores for assessing disease severity and risk stratification.7 Severe AH is defined as a MELD ≥21 or DF >32 and is associated with significant short-term mortality (30% at 1-month, 30-50% at 90 days, and >50% past 1 year).8 The majority of existing and ongoing studies on AH prognosis and future therapies have been developed in patients meeting these thresholds. Conversely, patients with MELD <21 or DF <32 are traditionally classified as having “nonsevere” or “moderate” AH. Mortality in patients with moderate AH has been observed to be as high as 3-7% at 1-3 months and 13-20% at the 1-year mark.9 This represents an overlooked population whose incidence is likely underestimated given many of these patients often present with mild symptoms that might not necessarily warrant hospitalization.

Our understanding of the diagnosis and pathogenesis of AH continues to evolve. However, there remains a paucity of effective therapies tailored towards its treatment, leaving alcohol abstinence and nutritional support as the long-term bedrocks of therapy. In severe AH, glucocorticoids have been found to improve 30-day mortality without improvement in longer term mortality.10 A recent study consisting of a large international cohort of 3380 patients revealed glucocorticoid therapy improved 30-day mortality in AH patients with MELD >20, with an even greater survival benefit being observed in patients with MELD scores of 25-39.11 Unfortunately, glucocorticoids remain a crude and imperfect therapeutic tool, often predisposing patients to increased infections and other well-documented side effects. There is also no conclusive evidence that glucocorticoids significantly improve survival in AH patients beyond 1 month. In this review, we will summarize the current management of AH and discuss novel therapies currently under investigation in which preliminary results from randomized clinical trials (RCTs) have shown benefit.

Current Management Guidelines

A summary of the most recent society guidelines for the management of AH is summarized in Table 2.12-14

Table 2. Summary of society guidelines for the management of AH

Alcohol abstinence

Alcohol abstinence remains the cornerstone of long-term AH management given its main pathophysiologic mechanism is related to liver toxicity from excessive alcohol consumption. Although there is a  lack of survival data in severe AH patients, abstinence has been found to be independently associated with long-term prognosis in moderate AH and is the only intervention thus far to increase 6-month survival.15 Many patients diagnosed with severe AH also concurrently suffer from significant alcohol use disorder (AUD). High rates of relapse of alcohol consumption shortly after recovery from AH are common complications that place patients at high-risk for repeated episodes of AH and thus worsen both short- and long-term prognosis. Despite this clinical challenge, achieving complete alcohol abstinence remains the goal for all AH and AUD patients.

Integrated addiction treatment incorporating motivational interviewing, pharmacological therapies, and cognitive behavioral therapy (CBT) have become the mainstay of helping patients achieve alcohol abstinence.16 Naltrexone, disulfiram, and acamprosate remain the only US Food and Drug Administration (FDA)-approved pharmacologic drugs available to treat AUD in the outpatient setting. However, patients with severe AH associated with significant liver dysfunction are likely not great candidates for these drugs. Additionally, despite their efficacy, only 10% of those with AUD receive any form of treatment, and less than 1% of those with AUD receive any FDA-approved medications.16 Other pharmacologic therapies such as gabapentin, baclofen and topiramate are currently prescribed off-label and remain under investigation.

Nutritional support

There is a high prevalence of malnutrition among patients with AH, with recent literature finding almost all patients with severe AH possessing some component of malnourishment.17 The degree of malnutrition often correlates with the clinical severity of liver dysfunction and increases the risk of infections and death, especially in patients with concomitant decompensated liver failure. Thus, early assessment of nutritional status and ensuring adequate caloric, protein, vitamin, and electrolyte intake to prevent progression to sarcopenia are essential to overall AH treatment.

Oral and enteral nutritional support are preferred in all patients with AH regardless of severity. Patients with severe AH often present with extremely poor oral intake and inadequate caloric and protein goals. Updated guidelines recommend a high-protein, high-energy diet consisting of 1.2-1.5 g/kg protein and 35-40 Kcal /kg calories per day.18

Liver transplantation

Patients with severe AH unresponsive to medical therapy were historically deemed ineligible for liver transplantation due to the lack of a minimum duration of sobriety. However, a 2011 landmark study by Mathurin et al. completely shifted this paradigm when it demonstrated early liver transplantation significantly improved 6-month survival post-transplant compared to a historical cohort (77% vs 23%).19 The previous “6 months of sobriety” rule was subsequently rejected due to the lack of supporting scientific evidence and clear survival benefit from early liver transplantation that has been replicated in follow-up studies.20 Current consensus formerly recognizes severe refractory AH as an indication for liver transplantation with considerations for social status, presence of active substance use, and disease insight, among other factors.

Promising Novel Therapies Under Investigation

Numerous studies in recent years have sought to investigate the efficacy of several biological molecules in the treatment of AH. The results of these studies are summarized in Table 3.

Table 3. Overview of pharmacological therapies under investigation for treatment of AH

Liver regeneration stimulation

DUR-928
DUR-928 acts as an epigenetic modulator that regulates the expression of multiple clusters of master genes involved in down-regulating lipotoxicity, stabilizes mitochondria, and reduces inflammatory and stress responses. A recent phase IIa, multicenter, open label, dose escalation trial in 19 AH patients found notable reductions in serum bilirubin levels at days 7 and 28 and MELD scores at day 28 with no reported adverse events.21 Additionally, Lille scores from 8 subjects with severe AH who received 30 or 90 mg DUR-928 were statistically significantly lower (p < 0.01) than those from subjects with severe AH treated with standard of care from a contemporaneous study. DUR-928 represents arguably the most promising novel therapy to date, and its therapeutic potential continues to be evaluated in an ongoing phase 2b, multicenter, randomized, doubleblinded, placebo-controlled trial (AHFIRM, NCT04563026).

Granulocyte colony-stimulating factor (G-CSF)
G-CSF is a glycoprotein that stimulates the bone marrow to mobilize hematopoietic CD34+ stem cells into the bloodstream. Animal models had previously demonstrated the potential for G-CSF administration to induce liver regeneration and improve survival. A recent meta-analysis of 7 RCTs (n=336) showed a 90-day survival benefit (OR 0.28, 95% CI: 0.09–0.88; p = 0.03) and reduced risk of developing infections in patients receiving G-CSF compared to placebo or pentoxifylline.22 However, despite its excellent safety profile, definite conclusions regarding the usefulness of G-CSF in AH cannot be made, as high heterogeneity was observed in the overall analysis caused by conflicting results between the Asian and European studies.

Inflammation amelioration

Interleukin (IL)-22
IL-22 plays a crucial role in hepatoprotection through its anti-apoptotic, regenerative, and anti-fibrotic effects. Its effects are mediated predominantly through the STAT3 signaling pathway and helps reduce hepatic injury by decreasing production of proinflammatory cytokines (e.g. tumor necrosis factor-α, IL-6) and ameliorating oxidative stress. A phase IIb trial studying the use of F-652 (an IL-22 analog) in 18 AH patients demonstrated a significant decrease in MELD score, proinflammatory cytokine markers, and serum aminotransferases while also observing an increase in hepatic regeneration markers at days 28 and 42 from baseline (p < 0.05).23 Ongoing clinical trials continue to evaluate the safety and efficacy of IL-22 analogs, but preliminary results are promising, especially with no significant associated adverse effects being reported thus far.

Infliximab
Infliximab is a TNF-α inhibitor that has been commonly used to treat chronic inflammatory pathologies such as rheumatic arthritis and inflammatory bowel disease. One systematic review of five studies found that 1-month mortality ranged from 10% to 17% in patients with severe AH who received a single dose of infliximab with or without prednisone compared to 38% in patients who received three doses of infliximab in combination with prednisone.24 While this review did note the potential for single-dose infliximab to act as an alternative agent with contraindications to steroids, further studies are needed to confirm these findings.

IL-1 receptor inhibitors
Anakinra is an IL-1 receptor inhibitor with anti-inflammatory properties. While it has been associated with a reduction in alcohol-associated hepatic steatosis, a recent phase IIb double-blind RCT studying the efficacy and safety of anakinra + zinc (A+Z) compared to prednisone was stopped early after a prespecified interim analysis showed prednisone was associated with higher 90-day overall survival (90% vs. 70%; hazard ratio for death = 0.34, 95% CI 0.14–0.83, p = 0.018) and transplant-free survival (88% vs. 64%; hazard ratio for transplant or death = 0.30, 95% CI 0.13–0.69, p = 0.004) than A+Z.25

Anti-oxidants

Metadoxine
Metadoxine (MTD) is an antioxidant that participates in glutathione synthesis and inhibits hepatic steatosis. An open-label study randomized 135 patients with severe AH into either daily prednisone (PDN) therapy, PDN+MTD three times daily therapy, pentoxifylline (PTX) three times daily therapy, or PTX+MTD three times daily for 1 month. MTD was found to significantly improve the survival rate at 3- (PTX+MTD 59.4% vs PTX 33.3%, p = 0.04; PDN+MTD 68.6% vs PDN 20%, p = 0.0001) and 6-months (PTX+MTD 50% vs PTX 18.2%, p = 0.01; PDN+MTD 48.6% vs PDN 20%, p = 0.003); MTD patients also maintained greater alcohol abstinence than the other study groups (74.5% vs 59.4%, p = 0.02).26 While RCTs with larger sample sizes are needed, these results signal that metadoxine is a safe therapy with potential benefits in AH patients.

Gut-liver axis

Fecal microbiota transplantation
(FMT)
Gut microbiota have long been theorized to play a role in the pathogenesis of AH and represents another promising research area of interest. A recent open-label study randomized 120 patients with severe AH into daily prednisolone therapy for 28 days or daily healthy donor FMT for seven days. FMT was found to significantly improve 90-day survival (75% vs 56.6%, p = 0.044, FMT HR = 0.528, 95% CI 0.279–0.998) and reduced the incidence of deaths due to infection (3.6% vs 19.3%, p = 0.01) at the 90-day mark.27 FMT continues to be a promising avenue for further clinical trials given its encouraging results in recent studies. However, given past reports of infections transmitted from FMTs triggering FDA alerts, more studies on the risks versus benefits of FMTs in immunocompromised AH populations (i.e. on or recently received steroid therapy) are needed. Additionally, the high cost of FMT is an additional potential barrier for widespread adoption.

Conclusions

AH is a severe complication of significant chronic alcohol use that is associated with high morbidity and mortality. Although our understanding of its pathogenesis through the gut-liver axis and inflammatory pathways has continued to deepen, there remains a scarcity of efficacious therapeutic options for its treatment. Alcohol abstinence and nutritional support remain the mainstays of long-term management. For patients presenting with acute severe AH, glucocorticoids are the pharmacological treatment of choice. However, there is limited evidence to suggest they improve survival beyond the immediate short-term, and their potent side effects with prolonged treatment present a significant challenge for many patients and practitioners. While many novel therapies under investigation have borne mixed or only early results thus far, liver regeneration stimulants like DUR-928 and advances in FMT represent promising avenues of research that bring hope that our collective lack of effective treatments for AH will soon come to an end.

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