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Emerging therapeutic regimens as alternatives to glucocorticoids for severe alcohol-associated hepatitis: a comprehensive review

Rahul Kumar1,2, Sakktivel Elangovan1, Sumeet K. Asrani3orcid
Clinical and Molecular Hepatology 2026;32(2):599-619.
Published online: February 20, 2026

1Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore

2Med-ACP, Duke-NUS Medical School, Singapore

3Department of Hepatology and Liver Transplantation, Baylor University Medical Center, Baylor Scott and White, Dallas, TX, USA

Corresponding author : Sumeet K. Asrani Department of Hepatology and Liver Transplantation, Baylor University Medical Center, Baylor Scott and White, 3410 Worth Street, Suite 860, Dallas, TX 75246, USA E-mail: Sumeet.asrani@BSWHealth.org

Editor: Nae-Yun Heo, Inje University Haeundae Paik Hospital, Korea

• Received: October 10, 2025   • Revised: February 15, 2026   • Accepted: February 19, 2026

Copyright © 2026 by The Korean Association for the Study of the Liver

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  • Severe alcohol-associated hepatitis (SAH) is the most aggressive form of alcohol-associated liver disease and is associated with very high short-term mortality. It is characterized by the acute onset of jaundice in the context of ongoing alcohol use, most commonly defined by a Maddrey’s discriminant function ≥32 or a model for end-stage liver disease score ≥20. Despite its increasing global burden and substantial healthcare costs, therapeutic options remain limited, and outcomes are poor. The severity of liver failure, systemic inflammation, infectious complications, and extrahepatic organ dysfunction determines the prognosis in SAH. The pathophysiology of SAH is multifactorial, involving direct hepatotoxicity from alcohol metabolites, oxidative stress, dysregulated immune activation, gut dysbiosis with increased intestinal permeability, impaired hepatic regeneration, and genetic susceptibility. These interrelated mechanisms culminate in an exaggerated inflammatory response driven by macrophage activation and cytokine release, resulting in hepatocellular injury and multi-organ failure. Glucocorticoids remain the guideline-recommended standard of care for selected patients; however, their benefit is limited to modest short-term survival gains, with high rates of non-response and infection. Numerous investigational therapies targeting inflammation, oxidative stress, liver regeneration, bile acid signalling, epigenetic regulation, and the gut-liver axis have been evaluated, with largely disappointing results. Emerging approaches, including interleukin-22 agonists and epigenetic modulators such as larsucosterol, show promise but require validation in well-designed trials. This review synthesizes current evidence on the definition, prognostic assessment, and pathophysiology of SAH, critically appraises existing and emerging therapies, and highlights the need for combination strategies, improved patient stratification, and personalized treatment approaches.
  • Keywords: Alcohol-associated hepatitis; Glucocorticoids; Alternative regimens; Novel therapy; Fecal microbiota transplant
Severe alcohol-associated hepatitis: definition, epidemiology, prognostic assessment of disease severity and pathophysiology
Alcohol-associated liver disease (ALD) is a leading global cause of end-stage liver disease, liver transplantation (LT), and mortality [1]. Alcohol-associated hepatitis (AAH) is a distinct clinical syndrome, characterised by the recent onset of jaundice with or without other signs of liver decompensation in patients with ongoing alcohol use [1,2]. Histologically, AAH is characterized by steatosis, hepatocyte ballooning, neutrophilic infiltration, and perisinusoidal fibrosis within the liver parenchyma [3]. While the term “alcoholic hepatitis” remains in common usage because of its historical prevalence, the adoption of “alcohol-associated” is increasingly recognized as a way to mitigate societal stigma associated with the condition [2]. Severe alcohol-associated hepatitis (SAH) represents the most aggressive form of ALD and is linked to very high short-term mortality, reaching up to 40% to 50% at 30 days [1,2,4,5]. SAH is typically defined by a Maddrey’s discriminant function (MDF) score ≥32 or a model for end-stage liver disease (MELD) score ≥20 in the presence of a compatible clinical history and presentation [1,2]. Additionally, alcohol use disorder (AUD) imposes a substantial economic burden [5].
Accurate assessment of disease severity and prognosis is paramount for guiding individualized therapeutic decisions in patients with SAH [3]. In SAH, the risk of mortality is related to a multitude of factors, including severity of liver disease, the attending complications and multi-organ failure, inflammatory response, and perhaps genetic polymorphism [6,7]. Several prognostic risk scores have been developed to assess disease severity, mortality, and pharmacologic intervention in patients with AAH; Table 1 lists the commonly used risk scores. These scores may be stratified as “static,” predicting prognosis at specific time points, or “dynamic,” assessing mortality risk across varied time intervals and the response to implemented therapy. Pre-treatment scores that measure the severity of AAH, such as the MDF, MELD, age, bilirubin, international normalized ratio, creatinine (ABIC score), and the Glasgow alcoholic hepatitis score, all reliably forecast short-term mortality [4,8-11].
Early improvement in liver function with glucocorticoids (GCs) is associated with lower short-term mortality. This can be assessed by recalculating static prognostic models after a short period or by using the Lille model, which measures treatment response. A change of 2 or more points in the MELD or Glasgow AH score, or a change in bilirubin after 7 days, predicts in-hospital mortality. The Lille model is more accurate than repeating static prognostic scores and helps identify response patterns: full, partial, or null, each with different early death risks. A Lille score of 0.45 is considered the optimal cut-off for differentiating responders from non-responders to GC therapy; a score >0.45 at 4 days or 7 days triggers GC discontinuation [11,12]. Additionally, a new model that combines both the baseline MELD and 7-day Lille score demonstrated superiority over models relying solely on baseline data for predicting prognosis in SAH [13].
The pathogenesis of SAH is complex and involves multiple intertwined pathways that contribute to hepatocellular injury, inflammation, cell death, and impaired capacity for liver regeneration [14]. Direct hepatotoxicity from alcohol metabolites, such as acetaldehyde, and reactive oxygen species (ROS) causes cellular damage [15]. Gut dysbiosis and increased intestinal permeability play a central role, triggered by activation of innate immune responses [16-19]. This inflammatory cascade, characterized by the release of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), drives hepatocellular injury and liver failure [18,19]. Chronic alcohol exposure and the ongoing inflammatory milieu impair the liver’s regenerative capacity, hindering the ability of hepatocytes to proliferate and repair the extensive damage, which is a significant factor in disease progression and poor outcomes [20]. Emerging evidence highlights the genetic and epigenetic factors that influence individual susceptibility and disease severity [21,22].
Each of these unique pathways, systemic and hepatic inflammation, oxidative stress and metabolic dysfunction, gutliver axis disruption, impaired hepatic regeneration, and genetic predisposition, serves as a potential target for therapeutic intervention. This review critically evaluates the current standard of care (SOC) and synthesizes the preclinical insights and clinical trial data, examining both successes and failures to highlight challenges in drug development.
Current standard of care: glucocorticoids – mechanism, efficacy, and limitations
Glucocorticoids, such as prednisolone, are recommended by the American Association for the Study of Liver Diseases and European Association for the Study of the Liver guidelines for SAH [1,2]. In theory, GCs help treat SAH through their anti-inflammatory properties; however, the exact mechanism remains unclear. Upon entering target cells, GCs bind to the glucocorticoid receptor (GR), which then translocates into the nucleus to modulate gene transcription [23]. The anti-inflammatory actions of GCs are mediated through transrepression, a process in which the ligand-activated GR, often as a monomer, interacts with and inhibits the activity of pro-inflammatory transcription factors, such as nuclear factor-kappa B (NF-κB) and activator protein-1 [23].
Despite their established role, the use of GCs to treat SAH has been controversial due to conflicting findings across studies and meta-analyses [24,25]. Prednisolone was associated with a non-significant decrease in 28-day mortality, with no change in mortality at 90 days or 1 year in a well-conducted study [26]. Another essential problem with the use of GCs is infection, which occurs in up to 40% of patients with SAH and is associated with increased mortality [6,27,28]. Furthermore, around 30% patients with SAH are null responders (Lille score >0.56) and do not benefit from GCs [11]. The limited, short-term efficacy of GCs, coupled with their significant contraindications and non-response rates, creates a profound unmet need for safer and effective therapeutic alternatives.
Pathophysiological targets for novel interventions
The complex pathogenesis of SAH offers many targets for developing therapies, focusing on pathways that cause liver injury and complications. Figure 1 shows mechanisms and potential targets for new therapeutic interventions. Past and ongoing trials have tested therapies targeting inflammatory signalling (IL-1 receptor antagonist, TNF-α inhibitor, and toll-like receptor-4 [TLR-4] inhibitor); oxidative stress (caspase inhibitor, n-acetylcysteine (NAC), apoptosis signal-regulating kinase-1 (ASK1) inhibitor, and omega-5 fatty acid); apoptosis and liver regeneration (IL-22 and granulocyte colony-stimulating factor [G-CSF]); the gut-liver axis (probiotics, FMT and antibiotics); bile acid homeostasis (obeticholic acid [OCA]) and modulation of specific signalling pathways with epigenetic modulators like larsucosterol. Of these options, several showed early promise but failed in either safety or efficacy trials. The key clinical trials discussed here are summarized in Table 2.
Emerging therapies for SAH

Agents targeting inflammatory signalling

Excessive inflammatory reaction and immune responses are the central drivers of SAH [29]. Targeting key inflammatory cytokines and pathways, such as IL-1β, TNF-α, and NF-κB, is a primary strategy to mitigate liver damage and systemic inflammatory response syndrome [29-32]. Multiple clinical trials have focused on therapies that target inflammation.
Anakinra and canakinumab: Preclinical studies showed that inhibiting IL-1β signalling can reduce features of ASH [33]. Consequently, agents that target the IL-1β pathway, such as anakinra (an IL-1 receptor antagonist) and canakinumab (a human anti-IL-1β monoclonal antibody), were investigated as potential treatment for SAH. Both anakinra and canakinumab failed to demonstrate meaningful clinical benefits [34,35]. In fact, anakinra was associated with higher rates of acute kidney injury and significantly lower survival than the SOC.34 Although canakinumab showed histological improvement, it did not reduce mortality or change Lille or MELD scores [35].
Etanercept, infliximab, and pentoxifylline: Clinical trials with etanercept, a soluble TNF-α receptor immunoglobulin constant fragment fusion protein that binds and neutralizes unbound serum TNF-α, were also disappointing [36,37]. Although the pilot study showed 92% survival at 30 days, a larger placebo-controlled study showed higher 30-day (34.6% vs. 22.7%; P=NS) and 180-day (57.7% vs. 22.7%; P=0.017) mortality with etanercept [36,37]. Infliximab is an anti– TNF-α monoclonal antibody that specifically binds and neutralizes the soluble TNF-α homotrimer and its membrane-bound precursor [38]. Infliximab has also been investigated in clinical studies to improve the outcomes in patients with SAH, either alone [39-41] or in combination with steroids [42,43]. No clear survival benefit was observed in patients with SAH. Similarly, large well-conducted studies with pentoxifylline, a non-specific TNF inhibitor, failed to show any mortality benefit over prednisolone alone [26,44].
Toll-like receptor-4 inhibitor: Although prior clinical trials with IL-1β and TNF-α have failed to show benefit in patients with SAH, a new trial involving a TLR-4 inhibitor is underway. TLR-4 is a key mediator of innate immune activation, activated by gut-derived LPS, leading to an exaggerated inflammatory response. TAK-242 is a small-molecule inhibitor of TLR-4 that showed promising results in murine models of LPS-induced acute-on-chronic liver failure (ACLF) [45]. TAK-242 is currently being evaluated in patients with SAH (NCT04620148) [46].

Agents targeting oxidative stress pathways

Alcohol and its metabolites generate ROS, increasing susceptibility to free-radical damage and depleting cellular antioxidant stores. Therapies that enhance antioxidant defences are crucial to counteract this injury [47,48]. Although there is a mechanistic rationale, antioxidant treatments have not demonstrated notable clinical benefits in the treatment of AH or SAH.
N-acetylcysteine: N-acetylcysteine (NAC) confers hepatoprotective effects primarily by restoring intracellular glutathione stores, thereby neutralizing ROS and mitigating oxidative stress and inflammation [49,50]. NAC has been assessed in several randomized controlled trials (RCTs) in SAH [51-54]. In a landmark RCT, 174 patients with SAH were randomized to receive prednisolone with intravenous (IV) NAC (85 patients) for 5 days or prednisolone with IV 5% glucose solution (89 patients) [54]. The combination therapy was associated with better survival at 1 month (8% vs. 24%, P=0.006), but not at 6 months (27% vs. 38%, P=0.07). Hepatorenal syndrome (P=0.02) and infections (P=0.001) were less frequent in the combination therapy at 6 months [54]. Overall, available evidence supports NAC’s safety and potential early advantage, but long-term benefit has not been consistently demonstrated. Ongoing phase 3 trials, PROCORNAC (NCT06956482) and NACAH (NCT03069300), are evaluating whether prolonged NAC therapy, with or without GC, improves outcomes [55,56].
ASK1 inhibitor: Selonsertib is a small molecule selective ASK-1 inhibitor that was investigated as a strategy to reduce oxidative stress-mediated hepatocyte apoptosis in SAH; however, selonsertib did not demonstrate either clinically meaningful improvement in MELD or short-term survival in a randomized phase 2 trial (NCT02854631) [57].
Omega-5 fatty acid: Omega-5 fatty acid is an antioxidant and a peroxisome proliferator-activated receptor gamma agonist. It helps to reduce lipid peroxidation and restores antioxidant enzyme activity. Additionally, it has also been shown to inhibit the expression of IL-6 and TNF-α. An ongoing study reported that oral administration of omega-5 (0.64 g/day) in combination with prednisolone reduced lipid oxidative stress at days 15 and 30; however, these differences were not statistically significant (NCT03732586) [58]. The published abstract, however, did not report on clinically translatable benefits [58].

Agents promoting liver regeneration

Granulocyte colony-stimulating factor: Granulocyte colony-stimulating factor (G-CSF) plays a crucial role in hematopoiesis by stimulating the bone marrow to produce and release neutrophils and stem cells (CD34+) into the bloodstream. It also induces the production of hepatocyte growth factor and stimulates the proliferation of hepatocyte progenitor cells [59,60]. G-CSF has been shown in translational studies to enhance hepatic regeneration [61,62] and clinical studies, predominantly from Asia, suggest a potential survival benefit in patients with SAH [63,64]. However, a large European trial failed to show a clear survival advantage [65]. A meta-analysis of seven RCTs, involving 396 patients, showed that G-CSF was linked to a lower risk of death at 90 days (odds ratio [OR] 0.28; 95% confidence interval [CI] 0.09– 0.88; P=0.03) and a decreased risk of developing infections (OR 0.21; 95% CI 0.08–0.55; P=0.001) [66]. However, a significant level of heterogeneity was observed (I²=80% for mortality, 73% for infection). In the subgroup analysis, Asian studies demonstrated a marked reduction in mortality (OR 0.15; 95% CI 0.08–0.28), while the European studies showed a trend toward increased mortality (OR 1.89; 95% CI 0.90–3.98). A recently published retrospective multicenter cohort study using a large research network (Tri-NetX) in the USA showed that G-CSF improved 90-day overall survival in patients with SAH by 74% [67].
The notable geographic discrepancy in G-CSF trial outcomes in SAH raises questions about the underlying explanatory factors. Differences in patient selection may be central; studies from Asia were typically small (n=40–60) and often enrolled younger patients with fewer comorbidities but more profound hepatic dysfunction at baseline, whereas Western cohorts were older, had more comorbidities, and showed evolving multi-organ failure. Baseline disease severity varied, with some trials including patients beyond the therapeutic “window” in which hepatic regeneration strategies could plausibly affect outcomes. Heterogeneity in SOC may also affect outcomes; GCs are used more consistently in Western settings, whereas Asian studies either excluded patients on GC or used heterogeneous regimens, potentially exaggerating the benefit of G-CSF. Differences in infection prophylaxis protocols are also significant. G-CSF-induced leucocytosis without strong antimicrobial strategies may raise infection-related complications, possibly diminishing survival benefits. Finally, the early literature mainly features small, single-centre positive trials, suggesting a potential publication bias, as neutral or negative studies are less likely to be published. Clarifying these factors is essential for future trial design, the optimization of inclusion criteria, and the identification of the clinical phenotypes and healthcare settings most likely to benefit from GCSF therapy.
Extracorporeal liver assist device: Cellular therapies may promote liver cell regeneration [68]. Hepatoblastoma-derived C3A cells, which express anti-inflammatory proteins and growth factors, were evaluated in an extracorporeal liver assist device (ELAD®) study as regenerative support to assess their impact on survival in patients with SAH. In the open-label, multicenter study, patients with SAH (MDF ≥32 and MELD score ≤35) were randomized to receive SOC with continuous ELAD® therapy for 3–5 days or SOC alone. The overall survival at 90 days did not differ significantly in the intention-to-treat analysis (51.0 vs. 49.5%). The prespecified secondary analysis showed a trend towards improved survival amongst patients with lower baseline MELD scores (<28) and younger age. ELAD®, however, remains an investigational therapy [69].
Therapeutic plasma exchange: Therapeutic plasma exchange (TPE) has emerged as a potential adjunct strategy in SAH, particularly when complicated by ACLF or when GC treatment is ineffective or contraindicated. TPE nonspecifically removes inflammatory cytokines, immune mediators, and toxic metabolites that cause systemic inflammation and organ dysfunction, aiding hepatic recovery or serving as a bridge to LT. A retrospective study reported better one-year transplant-free survival with TPE plus GC versus SOC in SAH, with hazard ratios favoring TPE across multiple time points [70]. Another study indicates that TPE can reduce bilirubin and severity scores and may be associated with lower medium-term mortality in alcohol-related ACLF not responding to SOC [71]. Importantly, no large, definitive trial has yet established the efficacy of TPE in SAH, though a randomized study comparing TPE with SOC is currently recruiting (NCT06355726) [72].
Interleukin-22 agonists: Interleukin-22 (IL-22), a member of the IL-10 cytokine family, is involved in tissue repair, anti-apoptotic signalling, and inflammatory modulation. It is primarily produced by innate lymphoid cells and exerts hepatoprotective effects by activating the Jak1/Tyk2-STAT3 pathway. IL-22 may also strengthen the gut barrier, reducing translocation of microbial products that exacerbate liver inflammation [73,74]. The regenerative capacity is particularly relevant given that hepatocyte proliferation is often suppressed in SAH [73]. Unlike classical pro-inflammatory cytokines such as TNF-α or IL-1β, IL-22 does not directly activate immune cells, thereby reducing the risk of inducing systemic inflammation [75]. Among IL-22–based therapies, the most extensively investigated agent is F-652, a recombinant fusion protein. In a phase 2 study, 18 patients with moderate to severe AH (MELD:11-28) were treated with two doses of F-652. In this study, F-652 was found to be safe and showed improvements in Lille and MELD scores, reductions in inflammatory markers, and a 42-day survival rate of 94.4%, much higher than that of historical controls [76]. Given the potentially broad reparative effects, IL-22 agonism represents a highly rational target in AH. Building on these findings, a prospective, multicenter trial of F-652 in SAH is currently underway to further evaluate its efficacy (NCT07060638) [77].

Agents targeting the gut microbiome and the gutliver axis

Alcohol consumption disrupts the intestinal mucosal barrier, leading to dysbiosis and increased gut permeability. This facilitates bacterial translocation and the entry of gutderived toxins (e.g., LPS) into the portal circulation, activating hepatic immune cells and exacerbating liver inflammation. Modulating the gut microbiome and restoring gut barrier integrity are key therapeutic avenues, and several microbiome-targeted strategies have been explored [19,78,79].
Probiotics: Probiotics are live microorganisms that, in adequate amounts, confer health benefits on the host, primarily by modulating the intestinal microbiota [80]. This modulation is hypothesized to reduce intestinal endotoxemia, a key driver of SAH [81]. A proof-of-concept study demonstrated that probiotics can restore the neutrophil phagocytic function in cirrhosis, possibly by modulating IL-10 secretion and TLR-4 expression [82]. Another RCT showed that daily oral Lactobacillus rhamnosus GG (LGG) supplementation resulted in significant improvements in MELD score at 1 month in patients with AAH. Notably, patients receiving LGG showed a significant decrease in alcohol consumption at 6 months compared to the placebo [83]. Ongoing studies continue to explore probiotic therapy in AH. A randomized, parallel-group trial (NCT05178069) is assessing the effects of a 6-month LGG regimen on liver injury and reducing heavy drinking in patients with AUD and moderate AH [84]. Another RCT (NCT03863730) is investigating the effects of probiotics on alcohol-related gut dysbiosis and the progression of the disease [85].
Faecal microbiota transplantation: Faecal microbiota transplantation (FMT) is an emerging therapy of transferring healthy donor intestinal microbiota into the gastrointestinal tract of a patient [86]. FMT may correct dysbiosis, which plays a critical role in the pathogenesis of SAH [87]. In a pilot study, FMT was administered to steroid-ineligible patients with SAH, demonstrating the feasibility and survival of 87.5% in the FMT group vs. 33.3% in historical controls (P=0.018) at 1-year [88]. A few other open-label studies, mainly from India, reported improved short-term outcomes with FMT, but the inclusion criteria and comparator arms were not consistent [89,90]. Despite the promising short-term outcomes, evidence for sustained benefit is not robust. Of late, a prospective European study also showed that FMT reduced 30-day mortality, particularly in patients with MELD score ≤30, MDF ≤90, and ACLF grade <2 [91]. The current evidence base is constrained by small sample sizes, heterogeneous study populations (e.g., inclusion of ACLF subgroups), and variability in FMT protocols (donor selection, delivery method, dosing). Additionally, most studies are open-label and unblinded, raising concerns about bias and limited generalizability. Furthermore, most FMT studies in SAH originate in India, raising questions about generalizability of the results to populations with different gut microbiome profiles, dietary patterns, and healthcare systems.
Antibiotics: Patients with SAH are at high risk of bacterial infection, which further contributes to the development of multi-organ failure and mortality [92]. Rifaximin is a non-absorbable antibiotic that modulates the intestinal microflora by influencing the gut-liver axis [93,94]. A recent open-label RCT investigated the effects of adding rifaximin to SOC in patients with SAH [95]. No significant differences in the 6-month LT-free survival or liver-related complications were found (P=0.502). This study, however, was limited by its small sample size, open-label design without a placebo, and baseline imbalance with sicker patients in the rifaximin arm (higher MELD). Pentoxifylline was permitted as standard therapy at study initiation, though later shown to be ineffective; subgroup analyses suggest its use did not alter outcomes. Additionally, many patients received concomitant antibiotics, warranting future investigation into how infection burden and antibiotic type may influence treatment effect. Another trial assessing the addition of amoxicillinclavulanate to prednisolone in patients with SAH found no benefit in 2-month survival compared with prednisolone alone [96].

Agents targeting bile acid homeostasis

Dysregulated bile acid metabolism contributes to liver injury and disrupts lipid homeostasis, correlating with disease severity in SAH. Farnesoid X receptor (FXR) is a nuclear receptor that regulates bile acid metabolism, inflammation, and lipid homeostasis as a master regulator [97]. Targeting FXR aims to restore homeostasis, reduce inflammation, and support hepatocyte function [97-99].
Obeticholic acid: Obeticholic acid (OCA) is a selective FXR agonist that is over 100 times more potent than the endogenous ligands [100]. By activating FXRs in both the intestine and the liver, OCA is hypothesized to lessen liver exposure to toxic bile acids, leading to anti-inflammatory and anti-fibrotic effects [99,100]. However, a phase 2 trial to evaluate safety and efficacy of OCA in patients with moderately severe AH was prematurely terminated due to concerns regarding hepatotoxicity associated with OCA (NCT 02039219) [101]. INT-787 (Next-Gen FXR Agonist) is a compound with enhanced FXR selectivity and solubility compared to OCA and has entered clinical trials for SAH. The Phase 2a FRESH study (NCT05639543) is assessing the safety, tolerability, and preliminary efficacy of INT-787 [102].

Agents targeting modulation of specific signalling pathways

Larsucosterol: Larsucosterol is an endogenous sulfated oxysterol that inhibits DNA methyltransferase. It is believed to stabilize mitochondria, reduce lipotoxicity, regulate inflammatory and stress responses, and promote cell survival [103]. A phase 2a pilot demonstrated safety and favourable improvements in liver function compared with matched SOC controls [104]. In a phase 2b trial, 307 patients with SAH were randomly assigned 1:1:1 to receive 30 mg or 90 mg larsucosterol or placebo. The dose was repeated after 72 hours if patients remained hospitalized (NCT04563026) [105]. All patients received SOC as determined by the investigators; patients in the larsucosterol group did not receive GCs but instead received a matching placebo. The composite primary endpoint was the difference in 90-day mortality or LT, which the trial did not meet. In a post-hoc subgroup analysis, a 90-day mortality benefit was observed in patients from the USA, raising the possibility that geographic location, timing of treatment, or other factors may modify the therapeutic effect. Other potential confounding factors, such as differences in SOC, patient selection criteria, and GC use patterns, cannot be ruled out. Furthermore, multiple subgroup analyses increase the risk of type 1 error. Larger, more definitive Phase 3 trials are anticipated to clarify its efficacy.

LT as a salvage therapy for SAH

LT represents the ultimate therapeutic option for patients with end-stage liver disease, including a subset of patients with SAH who are unresponsive to medical therapies. Historically, LT for ALD has been controversial, partly due to perceptions of ALD being a “self-inflicted” condition [106]. A long-standing practice has been the “six-month rule,” which requires at least 6 months of alcohol abstinence before LT evaluation [1,2]. However, evidence supporting this as a sole predictor of poor post-transplantation outcome and relapse has been limited [2,107]. Recent studies have demonstrated excellent results of LT in carefully selected patients with SAH [1,2,108]. The acceptance of early LT (ELT) for selected SAH patients represents a significant paradigm shift, offering a life-saving option for those who fail medical management.
The QuickTrans trial aimed to assess the risk of alcohol relapse at 2 years post-LT. The trial consisted of 3 groups: first, selected patients for ELT; second, patients who were not eligible for LT; and third, patients undergoing LT following 6-month abstinence from alcohol [109]. The trial demonstrated a significant survival benefit with ELT in patients with SAH compared to non-transplant controls. Survival in the ELT group was similar to that in the standard LT group (post-6-month abstinence rule) [109]. In the same study, though, alcohol relapse and binge drinking were more frequent after ELT compared to the standard LT group [109]. Another single-centre retrospective study reported that although ELT achieves comparable 10-year survival to other indications, higher rates of post-transplant alcohol use were observed [110]. Thus, a nuanced, evidence-based approach to ELT and standard LT should be taken, guided by dynamic biological scoring and rigorous psychosocial profiling.

Multidisciplinary approach to the management of SAH

The traditional model of care for AH often involved a “siloed” approach; however, in recent times, the management of AH has evolved from a passive, supportive approach to an active, multidisciplinary strategy (MDT). The integration of hepatology as the medical anchor with addiction medicine, nutrition, and palliative care addresses the “dual pathology” of liver failure and AUD, improving both survival and long-term sobriety [111,112]. The MDT should not merely be a referral network but an integrated operational unit in which specialists co-manage the patient in real time. The MDT must distinguish between patients who will recover with medical therapy, those requiring ELT, and those for whom aggressive care is futile. This requires a dual stratification system: biological, such as MDF, Lille, and MELD, to predict mortality, and psychosocial, such as the Stanford Integrated Psychosocial Assessment for Transplantation tool and the sustained alcohol use post-liver transplant score [113,114].
A frequent source of clinical confusion is the overlap between “supportive care” and “palliative care.” In the context of SAH, these terms denote distinct operational frameworks. Supportive care refers to the standard medical management aimed at maintaining physiological homeostasis and reversing organ failure. It is “supportive” in that it supports organ function while the liver regenerates. Palliative care is a specialized medical discipline focused on relieving suffering and improving quality of life. It is not synonymous with end-of-life care and can/should be delivered concurrently with curative treatments, including transplant evaluation [115]. Clinicians should adopt a holistic view; treating SAH with available pharmacotherapy, treating the addiction problem with pharmacotherapy and counselling, and treating the person with palliative care. This MDT model represents the only viable path forward for reducing the devastating morbidity and mortality of SAH. Figure 2 outlines the proposed management algorithm for SAH.
AUD treatment after discharge
Underlying AUD is the major driver of SAH, and abstinence remains the fundamental principle [116,117]. Return to drinking after treatment for SAH is high, with 60–80% and 70–80% of patients returning to drinking after 3 and 12 months, respectively [118]. Effective pharmacotherapy combined with psychological support improves abstinence; however, many trials have excluded patients with significant liver impairment, creating real-world uncertainty about safety and prescription practices. Naltrexone, acamprosate, and disulfiram are approved for the treatment of AUD. Naltrexone is a mu-opioid receptor antagonist that modifies the hypothalamic–pituitary–adrenal axis, which works by curbing the reward feeling of alcohol. Due to its hepatic metabolism, historical concerns about hepatotoxicity have limited its use [119]. Although guidelines suggest cautious use in compensated cirrhosis and avoidance in decompensated liver disease, a large retrospective cohort study found no significant drug-induced liver injury from naltrexone and no attributed decompensations, supporting its use in both compensated and decompensated cirrhosis with close monitoring [120,121]. Acamprosate modulates glutamate neurotransmission at metabotropic glutamate receptors, which reduces alcohol cravings [122]. Acamprosate has no hepatic metabolism and is renally eliminated, making it an attractive option in liver disease. Meta-analyses in general AUD cohorts support efficacy in maintaining abstinence with a favourable safety profile [123]. In patients with cirrhosis, retrospective real-world data suggest fewer unplanned admissions with acamprosate than with baclofen, with no major hepatotoxicity [124]. Renal function, however, is critical for acamprosate use, as it is renally cleared. Dose adjustments are required in patients with low glomerular filtration rate (GFR) and are contraindicated in GFR <30 mL/min/1.73 m2. Disulfiram works by increasing acetaldehyde accumulation, causing unpleasant effects. Disulfiram is not recommended in cirrhosis due to well-documented serious hepatotoxicity and rare liver failure [121]. Baclofen, a GABA-B agonist, is the most studied non-FDA-approved drug in cirrhosis. It is mainly cleared by the kidneys, with minimal hepatic metabolism, and is suitable for both compensated and decompensated cirrhosis. A trial showed higher abstinence rates (OR 6.3) versus placebo, and studies indicate it is acceptably safe, though side effects like fatigue and sedation may be problematic, especially in hepatic encephalopathy [125,126].

Challenges and future directions

The development of effective alternative therapies for SAH is hampered by several methodological challenges inherent in clinical trials for this complex condition. The observed conflicting results across various trials, such as those for GCs and G-CSF, highlight significant heterogeneity within patient populations, variations in disease severity at presentation, and inconsistencies in trial design. This variability makes it difficult to draw definitive conclusions and translate research findings into consistent clinical practice. Prednisolone, usually 40 mg daily for four weeks, remains the recommended treatment for SAH, though the ideal dose is still debated. The recent STASH trial found that using prednisolone either as a fixed dose (40 mg/day for 4 weeks) or as a tapering dose (starting at 40 mg/day for 1 week, then tapering by 10 mg each week) resulted in similar mortality rates while reducing infection rates at 90 days [127]. These results suggest that a tapering regimen of GC therapy could be an alternative without the loss of efficacy in patients with SAH. The complex, multi-factorial pathogenesis of SAH, with intertwined pathways, strongly suggests that single-agent therapies may be insufficient to achieve sustained clinical benefit [14,31].
Future strategies would likely involve combination treatment strategies targeting inflammation, gut dysbiosis, and regeneration, as well as AUD. A promising new approach would be the use of dual-acting agents with hepatoprotective properties and central nervous system activity, thereby reducing alcohol consumption. In this context, glucagonlike peptide-1 receptor agonists (GLP1-RA) and fibroblast growth factor 21 (FGF-21) are promising. GLP1-RAs, developed to treat diabetes and obesity, have shown hepatoprotective and anti-inflammatory effects in preclinical models of AH [128-131]. The mechanism is believed to be centrally mediated, with GLP1 receptors expressed in brain regions associated with reward and addiction, such as the nucleus accumbens and ventral tegmental area [132]. A small RCT of semaglutide, a GLP1-RA, in individuals with AUD demonstrated significant reductions in alcohol intake, craving, and heavy drinking days over nine weeks, and another showed dulaglutide, also a GLP1-RA, reduces alcohol intake [133,134]. FGF-21 is an endocrine hormone that has been shown to protect against hepatic steatosis, inflammation, and fibrosis in animal models of AUD [135,136]. In parallel, it modulates reward-related neural pathways, reducing alcohol preference and intake in both animal studies and early-phase clinical trials [137,138]. GLP-1 RAs and FGF-21 form a promising dualtargeted therapy aligning with AH's pathophysiology. They target liver injury and alcohol behaviour, offering a holistic approach for those with AUD and ALD.
SAH remains a high-mortality phenotype of ALD, in which current GC-based therapy delivers only modest, short-term benefits and leaves a substantial therapeutic void. Advances in mechanistic understanding have revealed a multifactorial pathogenesis, characterised by dysregulated inflammation, disruption of the gut-liver axis, oxidative stress, impaired regeneration, and genetic susceptibility, each of which offers rational targets for intervention. Yet, translation from bench to bedside has been hindered by heterogeneous study designs, geographic variability, and the exclusion of clinically representative populations. Emerging biologically informed therapies such as F-652, larsucosterol, and FMT provide encouraging signals but require rigorous, globally harmonised evaluation. LT, possibly early, remains a viable option for patients not responding to medical management. Ultimately, improving outcomes will demand a shift toward precision phenotyping, the integration of addiction medicine, and multicenter trial frameworks that reflect the real-world complexity of disease. SAH must be approached not as a single entity, but as a dynamic syndrome in which biology, psychosocial factors, and multidisciplinary care intersect to determine survival.

Authors’ contributions

Rahul Kumar, Sakktivel Elangovan and Sumeet K Asrani drafted and edited the initial manuscript. Further editing and changes were made by Rahul Kumar and Sumeet K Asrani. All authors approve of the contents of the manuscript.

Conflicts of Interest

The authors have no conflicts to disclose.

Figure 1.
Pathophysiology and novel therapeutic targets for severe alcohol-associated hepatitis. Alcohol metabolism induces oxidative stress and hepatocyte injury, triggering DAMP release, inflammatory signalling, inflammasome activation, and impaired hepatic regeneration. In parallel, alcohol-related gut dysbiosis and increased intestinal permeability enhance the translocation of endotoxin via the gut-liver axis, further amplifying inflammation and injury. The schematic highlights therapeutic strategies targeting inflammation, oxidative stress, hepatic regeneration, bile acid homeostasis, and the gut-liver axis, encompassing both failed and ongoing clinical approaches. CYP-450, cytochrome P450 enzyme system; DAMPs, damage-associated molecular patterns; ELAD, extracorporeal liver assist device; FMT, faecal microbiota transplantation; G-CSF, granulocyte colony-stimulating factor; IL, interleukin; IL-R, interleukin receptor; LPS, lipopolysaccharide; PAMPs, pathogen-associated molecular patterns; TNF, tumor necrosis factor; TLR-4, toll-like receptor 4.
cmh-2025-1163f1.jpg
Figure 2.
Management algorithm for SAH. A multidisciplinary approach is essential for patients with SAH. On admission, evaluate disease severity with MELD and MDF scores. Initiate GC therapy for suitable patients. Provide nutritional therapy and monitor for bacterial and fungal infections. Use the Lille score at days 4–7 to assess GC response; those who do not improve should be evaluated for ELT. AUD harm-reduction strategies are crucial in management. AUD, alcohol use disorder; ELT, early liver transplant; GC, glucocorticoids; MDF, Maddrey discriminant function; MDT, multi-disciplinary care; MELD, model for end-stage liver disease; SAH, severe alcohol-associated hepatitis.
cmh-2025-1163f2.jpg
Table 1.
Prognostic scores commonly used for severe alcohol-associated hepatitis
Table 1.
Scores Purpose Key variables Timing Stratification Mortality horizon References
Maddrey’s discriminant function Severity/GC eligibility PT, bilirubin At admission ≥32=SAH 28–30 day Maddrey et al. [4]
MELD Mortality prediction/GC selection Bilirubin, INR, creatinine At admission and dynamic >20=SAH 90 day Kamath et al. [8]
Glasgow alcoholic hepatitis score Mortality prediction/GC selection Age, bilirubin, urea, INR, WBC At admission ≥9=high risk of mortality 28–84 day Forrest et al. [9]
Age-bilirubin-INRcreatinine Risk stratification Age, bilirubin, INR, creatinine At admission <6.71=low mortality; ≥9=high mortality 90 day–1 year Dominguez et al. [10]
Lille GC response Age, albumin, Δ bilirubin, creatinine, PT Day 4–7 ≥0.45=non-response to GC and higher mortality 180 days Louvet et al. [11]
MELD+Lille Dynamic prediction MELD+Lille Day 7 Best for discrimination and determining mortality 28–90 day Louvet et al. [13]

GC, glucocorticoid; INR, international normalised ratio; MELD, model for end stage liver disease; PT, prothrombin time; SAH, severe alcohol-associated hepatitis; WBC, white blood cell.

Table 2.
Alternative and emerging therapies for severe alcohol-associated hepatitis
Table 2.
Drug and key study Pathophysiological target Study design Year of publication or trial registration Study population and sample size Results Trial status/recommendation
Agents targeting anti-inflammatory signalling
 Anakinra [34] IL-1β receptor antagonist. Phase IIb RCT 2024 SAH (MELD=20–35) The trial was stopped early. Worse 90-day overall and transplant-free survival Failed/not recommended
 NCT04072822 SOC: 73
Anakinra: 74
 Canakinumab [35] IL-1β inhibitor monoclonal antibody. Phase IIb RCT 2025 Biopsy-confirmed SAH (MDF ≥32) and MELD ≤27 Histological improvement without affecting Lille score, MELD, or mortality Failed/not recommended
 NCT03775109 SOC: 28
Canakinumab: 29
 Etanercept [37] Binds and neutralizes the unbound serum TNF-α. Phase IIb RCT 2004 Moderate to severe AH (MELD >15) Higher rate of 6-month mortality in Etanercept group Failed/not recommended
 NCT: Not available SOC: 22
Etanercept: 26
 Infliximab [40] Anti-TNF-α. Neutralize TNF-α. Open-label, single-arm 2009 SAH (MDF ≥32) 1 month survival of 89% and 2 month survival of 68% Failed/not recommended
 NCT: Not available Infliximab: 19 patients
 Pentoxifylline [26] Non-specific TNF inhibitor Multicenter double-blind RCT 2015 SAH (MDF ≥32) No mortality benefit for pentoxifylline over GC either at 30 days or 12 months Failed/not recommended
 ISRCTN88782125 SOC: 276
GC+SOC: 277 Pentoxifylline+SOC: 276
GC+Pentoxifylline: 274
 TAK-242 [46] TLR-4 inhibitor Multicenter RCT Parallel assignment 2021 AAH Unknown Unknown
 NCT04620148
Agents targeting oxidative stress pathways
 N-acetylcysteine [54] NAC restores intracellular glutathione levels, counteracting ROS and mitigating oxidative stress. Multicentr RCT 2011 SAH (MDF ≥32) Mortality lower at 1 month but not at 3 months Not recommended, however can be used as short-term adjuncts
 NCT00863785 Control: SOC (GC): 89 HRS was less frequent in the SOC+NAC at 6 months
Intervention SOC (GC)+NAC: 85
 PROCORNAC NAC restores intracellular glutathione levels, counteracting ROS and mitigating oxidative stress. Multicentr RCT 2025 Awaited Awaited, expected in 2027 Not yet recruiting
 NCT06956482 [55] Parallel assignment
 NACAH NAC restores intracellular glutathione levels, counteracting ROS and mitigating oxidative stress. Randomized, open label, Parallel assignment 2015 Awaited Awaited Recruiting
 NCT03069300 [56]
 Selonsertib [57] ASK 1 Inhibitor Phase 2, multicenter 2019 SAH (MDF ≥32; MELD <30) Did not improve survival at 1,3 or 6 months Failed/not recommended
 NCT02854631 Control: (GC+placebo): 52
Intervention: GC+selonsertib: 52
 Omega-5 fatty acid [58] Antioxidant; P-PAR-Ýagonist Phase 2 2023 SAH (MDF ≥32) Reduced oxidative stress Unknown/not recommended
 NCT03732586 Control: (GC+placebo)=20 No mortality benefit reported
Intervention: (GC+omega-5 capsule)=20
Agents promoting liver regeneration
 Granulocyte colony-stimulating factor (G-CSF) [66] G-CSF stimulates the bone marrow to produce and release neutrophils and stem cells into the bloodstream. Meta-analysis of 7 RCT (5 from Asia, 2 from Europe) 2020 336 patients with AAH G-CSF reduced risk of death at 90 days in Asian but not in European studies No clear benefit across geographies
SOC (placebo/pentoxifylline): 199 Larger well controlled trials are needed.
SOC+G-CSF: 197 High heterogeneity between studies
 Extracorporeal liver assist device (ELAD) [69] Hepatoblastoma derived C3A cells can help prevent degeneration and facilitate recovery. Open-label multicenter RCT 2018 SAH (MDF ≥32, MELD <35) ELAD was safe but no difference in survival between ELAD or SOC Failed/not recommended
SOC: 107
 NCT01471028 ELAD+SOC: 96
 Therapeutic plasma exchange (TPE) [72] Non-specific removal of inflammatory cytokines, immune mediators, and toxic metabolites Open-label RCT 2024 TPE vs SOC Awaited, expected completion in 2025 Unknown
SAH: 80≥ MDF <120
 NCT06355726 Not suitable for liver transplant
 F-652 [76] IL-22 agonists. Hepatoprotective effects by activating the Jak1/ Tyk2-STAT3 pathway. Phase 2a 2019 AAH (MELD:11–28) Safe and improved inflammatory markers, MELD and 42-day survival of 94.4% Phase 3 trial results awaited
 NCT02655510 SOC+F652: 18
 ITAALD [77] IL-22 agonists. Hepatoprotective effects by activating the Jak1/Tyk2-STAT3 pathway. Multicentr double-blind RCT Phase 3 2025 2x2 factorial design Awaited Recruiting
 NCT07060638 Compare 90-day and 1-year survival
Agents targeting the gut microbiome and the gut-liver axis
 Probiotics (Lactobacillus rhamnosus GG [LGG]) [83] Altering intestinal microbiota with modulation of IL-10 secretion and TLR-4 expression. Phase 2 RCT 2023 Moderate AAH (MELD: 12–20) LGG lead to improved liver enzymes and reduced heavy drinking Larger studies needed/ Not recommended for SAH
SOC+placebo: 22
 NCT01922895 SOC+LGG: 24
 Probiotics (LGG) [84] Altering intestinal microbiota with modulation of IL-10 secretion and TLR-4 expression. Phase 2 RCT (LGG or placebo) 2022 AUD with heavy drinking Unknown Recruiting
 NCT05178069 8≤MELD≤19 Expected completion 2026
 SYN-ALD [85] Altering intestinal microbiota Randomized parallel assignment 2019 Heavy alcohol use and compensated advanced alcohol related liver disease. 24 weeks intervention Unknown Active, not recruiting
 Profermin and probiotics
 NCT03863730
 Faecal microbiota transplant (FMT) [88-91] Restoration of gut symbiosis/correct dysbiosis. Multiple Open-label RCT’s 2017–2024 Multiple studies, variable protocols Higher short-term survival in SAH (at 1 and 3 months) compared to SOC FMT is promising for short-term benefits. Larger trials are awaited/not recommended.
Small sample size
Inclusion: SAH and moderate AH No survival advantage at 6 months to 1 year
 Rifaximin [95] Modulating intestinal microflora and influencing the gut-liver axis. Open-label Placebo controlled RCT 2025 SAH (MDF ≥32) No significant differences in 6-month LT-free survival or liver-related complications Failed/not recommended.
 NCT02485106 SOC (GC or pentoxifylline)×4 week: 29
SOC (GC or pentoxifylline)×4 week+rifaximin: 21
 Amoxicillin-clavulanate [96] Influencing systemic bacterial load Multicenter, double-blind RCT 2023 SAH: (MDF ≥32; MELD ≥21) and Biopsy proven No difference in 2-month survival but infection rates lower in amoxicillin-clavulanate group Failed/not recommended
 NCT02281929 SOC (GC)+placebo: 147
SOC (GC)+amoxicillinclavulanate: 145
Bile acid homeostasis modulation
 Obeticholic acid (OCA) [101] OCA is hypothesized to lessen liver exposure to toxic bile acids Phase 2a 2020 AAH (MELD: 11–20) The trial was prematurely terminated due to hepatotoxicity associated with OCA. Failed/not recommended.
 NCT02039219
 INT-787 [102] Selective FXR agonist Phase 2a 2025 SAH: MDF ≥32 and ≤70 or MELD≥18 and ≤25 Ongoing Awaited
 NCT05639543 Exact sample size unknown
Agents targeting modulation of specific signalling pathways
 Larsucosterol [105] Epigenetic modulator, improves cell survival Phase 2a 2025 SAH (MDF>32); 307 patients randomized. Both doses well tolerated. No 90-day mortality benefit overall but improved 90-day survival in USA cohort. Larger phase 3 trial required.
 NCT04563026 1:1:1 to LAR 30 mg LAR 90 mg or placebo.

AAH, alcohol-associated hepatitis; ALD, alcohol-associated liver disease; ELAD, extracorporeal liver assist device; FMT, faecal microbiota transplant; FXR, farnesoid X receptor; GC, glucocorticoid; G-CSF, granulocyte colony-stimulating factor; HRS, hepatorenal syndrome; IL-1β, interleukin-1 beta; IL-10, interleukin-10; MDF, Maddrey’s discriminant function; MELD, model for end-stage liver disease; NAC, N-acetylcysteine; OCA, obeticholic acid; RCT, randomized controlled trial; ROS, reactive oxygen species; SAH, severe alcoholassociated hepatitis; SOC, standard of care; TNF-α, tumor necrosis factor alpha; TLR-4, toll-like receptor-4.

AAH

alcohol-associated hepatitis

ALD

alcohol-associated liver disease

AUD

alcohol use disorder

CYP-450

cytochrome P450 enzyme system

DAMPs

damageassociated molecular patterns

ELAD

extracorporeal liver assist device

ELT

early liver transplant

FMT

fecal microbiota transplant

FXR

farnesoid X receptor

GC

glucocorticoid

G-CSF

granulocyte colony stimulating factor

HRS

hepatorenal syndrome

IL

interleukin

IL-R

interleukin receptor

INR

international normalised ratio

LPS

lipopolysaccharide

MDF

Maddrey’s discriminant function

MDT

multi-disciplinary care

MELD

model for end-stage liver disease

NAC

n-acetylcysteine

OCA

obeticholic acid

PAMPs

pathogen-associated molecular patterns

PT

prothrombin time

RCT

randomized controlled trial

ROS

reactive oxygen species

SAH

severe alcoholassociated hepatitis

SOC

standard of care

TLR-4

toll-like receptor-4

TNF-α

tumor necrosis factor alpha
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Emerging therapeutic regimens as alternatives to glucocorticoids for severe alcohol-associated hepatitis: a comprehensive review
Clin Mol Hepatol. 2026;32(2):599-619.   Published online February 20, 2026
DOI: https://doi.org/10.3350/cmh.2025.1163
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Emerging therapeutic regimens as alternatives to glucocorticoids for severe alcohol-associated hepatitis: a comprehensive review
Clin Mol Hepatol. 2026;32(2):599-619.   Published online February 20, 2026
DOI: https://doi.org/10.3350/cmh.2025.1163
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Emerging therapeutic regimens as alternatives to glucocorticoids for severe alcohol-associated hepatitis: a comprehensive review
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Figure 1. Pathophysiology and novel therapeutic targets for severe alcohol-associated hepatitis. Alcohol metabolism induces oxidative stress and hepatocyte injury, triggering DAMP release, inflammatory signalling, inflammasome activation, and impaired hepatic regeneration. In parallel, alcohol-related gut dysbiosis and increased intestinal permeability enhance the translocation of endotoxin via the gut-liver axis, further amplifying inflammation and injury. The schematic highlights therapeutic strategies targeting inflammation, oxidative stress, hepatic regeneration, bile acid homeostasis, and the gut-liver axis, encompassing both failed and ongoing clinical approaches. CYP-450, cytochrome P450 enzyme system; DAMPs, damage-associated molecular patterns; ELAD, extracorporeal liver assist device; FMT, faecal microbiota transplantation; G-CSF, granulocyte colony-stimulating factor; IL, interleukin; IL-R, interleukin receptor; LPS, lipopolysaccharide; PAMPs, pathogen-associated molecular patterns; TNF, tumor necrosis factor; TLR-4, toll-like receptor 4.
Figure 2. Management algorithm for SAH. A multidisciplinary approach is essential for patients with SAH. On admission, evaluate disease severity with MELD and MDF scores. Initiate GC therapy for suitable patients. Provide nutritional therapy and monitor for bacterial and fungal infections. Use the Lille score at days 4–7 to assess GC response; those who do not improve should be evaluated for ELT. AUD harm-reduction strategies are crucial in management. AUD, alcohol use disorder; ELT, early liver transplant; GC, glucocorticoids; MDF, Maddrey discriminant function; MDT, multi-disciplinary care; MELD, model for end-stage liver disease; SAH, severe alcohol-associated hepatitis.

Figure 1.

Figure 2.

Emerging therapeutic regimens as alternatives to glucocorticoids for severe alcohol-associated hepatitis: a comprehensive review
Scores Purpose Key variables Timing Stratification Mortality horizon References
Maddrey’s discriminant function Severity/GC eligibility PT, bilirubin At admission ≥32=SAH 28–30 day Maddrey et al. [4]
MELD Mortality prediction/GC selection Bilirubin, INR, creatinine At admission and dynamic >20=SAH 90 day Kamath et al. [8]
Glasgow alcoholic hepatitis score Mortality prediction/GC selection Age, bilirubin, urea, INR, WBC At admission ≥9=high risk of mortality 28–84 day Forrest et al. [9]
Age-bilirubin-INRcreatinine Risk stratification Age, bilirubin, INR, creatinine At admission <6.71=low mortality; ≥9=high mortality 90 day–1 year Dominguez et al. [10]
Lille GC response Age, albumin, Δ bilirubin, creatinine, PT Day 4–7 ≥0.45=non-response to GC and higher mortality 180 days Louvet et al. [11]
MELD+Lille Dynamic prediction MELD+Lille Day 7 Best for discrimination and determining mortality 28–90 day Louvet et al. [13]
Drug and key study Pathophysiological target Study design Year of publication or trial registration Study population and sample size Results Trial status/recommendation
Agents targeting anti-inflammatory signalling
 Anakinra [34] IL-1β receptor antagonist. Phase IIb RCT 2024 SAH (MELD=20–35) The trial was stopped early. Worse 90-day overall and transplant-free survival Failed/not recommended
 NCT04072822 SOC: 73
Anakinra: 74
 Canakinumab [35] IL-1β inhibitor monoclonal antibody. Phase IIb RCT 2025 Biopsy-confirmed SAH (MDF ≥32) and MELD ≤27 Histological improvement without affecting Lille score, MELD, or mortality Failed/not recommended
 NCT03775109 SOC: 28
Canakinumab: 29
 Etanercept [37] Binds and neutralizes the unbound serum TNF-α. Phase IIb RCT 2004 Moderate to severe AH (MELD >15) Higher rate of 6-month mortality in Etanercept group Failed/not recommended
 NCT: Not available SOC: 22
Etanercept: 26
 Infliximab [40] Anti-TNF-α. Neutralize TNF-α. Open-label, single-arm 2009 SAH (MDF ≥32) 1 month survival of 89% and 2 month survival of 68% Failed/not recommended
 NCT: Not available Infliximab: 19 patients
 Pentoxifylline [26] Non-specific TNF inhibitor Multicenter double-blind RCT 2015 SAH (MDF ≥32) No mortality benefit for pentoxifylline over GC either at 30 days or 12 months Failed/not recommended
 ISRCTN88782125 SOC: 276
GC+SOC: 277 Pentoxifylline+SOC: 276
GC+Pentoxifylline: 274
 TAK-242 [46] TLR-4 inhibitor Multicenter RCT Parallel assignment 2021 AAH Unknown Unknown
 NCT04620148
Agents targeting oxidative stress pathways
 N-acetylcysteine [54] NAC restores intracellular glutathione levels, counteracting ROS and mitigating oxidative stress. Multicentr RCT 2011 SAH (MDF ≥32) Mortality lower at 1 month but not at 3 months Not recommended, however can be used as short-term adjuncts
 NCT00863785 Control: SOC (GC): 89 HRS was less frequent in the SOC+NAC at 6 months
Intervention SOC (GC)+NAC: 85
 PROCORNAC NAC restores intracellular glutathione levels, counteracting ROS and mitigating oxidative stress. Multicentr RCT 2025 Awaited Awaited, expected in 2027 Not yet recruiting
 NCT06956482 [55] Parallel assignment
 NACAH NAC restores intracellular glutathione levels, counteracting ROS and mitigating oxidative stress. Randomized, open label, Parallel assignment 2015 Awaited Awaited Recruiting
 NCT03069300 [56]
 Selonsertib [57] ASK 1 Inhibitor Phase 2, multicenter 2019 SAH (MDF ≥32; MELD <30) Did not improve survival at 1,3 or 6 months Failed/not recommended
 NCT02854631 Control: (GC+placebo): 52
Intervention: GC+selonsertib: 52
 Omega-5 fatty acid [58] Antioxidant; P-PAR-Ýagonist Phase 2 2023 SAH (MDF ≥32) Reduced oxidative stress Unknown/not recommended
 NCT03732586 Control: (GC+placebo)=20 No mortality benefit reported
Intervention: (GC+omega-5 capsule)=20
Agents promoting liver regeneration
 Granulocyte colony-stimulating factor (G-CSF) [66] G-CSF stimulates the bone marrow to produce and release neutrophils and stem cells into the bloodstream. Meta-analysis of 7 RCT (5 from Asia, 2 from Europe) 2020 336 patients with AAH G-CSF reduced risk of death at 90 days in Asian but not in European studies No clear benefit across geographies
SOC (placebo/pentoxifylline): 199 Larger well controlled trials are needed.
SOC+G-CSF: 197 High heterogeneity between studies
 Extracorporeal liver assist device (ELAD) [69] Hepatoblastoma derived C3A cells can help prevent degeneration and facilitate recovery. Open-label multicenter RCT 2018 SAH (MDF ≥32, MELD <35) ELAD was safe but no difference in survival between ELAD or SOC Failed/not recommended
SOC: 107
 NCT01471028 ELAD+SOC: 96
 Therapeutic plasma exchange (TPE) [72] Non-specific removal of inflammatory cytokines, immune mediators, and toxic metabolites Open-label RCT 2024 TPE vs SOC Awaited, expected completion in 2025 Unknown
SAH: 80≥ MDF <120
 NCT06355726 Not suitable for liver transplant
 F-652 [76] IL-22 agonists. Hepatoprotective effects by activating the Jak1/ Tyk2-STAT3 pathway. Phase 2a 2019 AAH (MELD:11–28) Safe and improved inflammatory markers, MELD and 42-day survival of 94.4% Phase 3 trial results awaited
 NCT02655510 SOC+F652: 18
 ITAALD [77] IL-22 agonists. Hepatoprotective effects by activating the Jak1/Tyk2-STAT3 pathway. Multicentr double-blind RCT Phase 3 2025 2x2 factorial design Awaited Recruiting
 NCT07060638 Compare 90-day and 1-year survival
Agents targeting the gut microbiome and the gut-liver axis
 Probiotics (Lactobacillus rhamnosus GG [LGG]) [83] Altering intestinal microbiota with modulation of IL-10 secretion and TLR-4 expression. Phase 2 RCT 2023 Moderate AAH (MELD: 12–20) LGG lead to improved liver enzymes and reduced heavy drinking Larger studies needed/ Not recommended for SAH
SOC+placebo: 22
 NCT01922895 SOC+LGG: 24
 Probiotics (LGG) [84] Altering intestinal microbiota with modulation of IL-10 secretion and TLR-4 expression. Phase 2 RCT (LGG or placebo) 2022 AUD with heavy drinking Unknown Recruiting
 NCT05178069 8≤MELD≤19 Expected completion 2026
 SYN-ALD [85] Altering intestinal microbiota Randomized parallel assignment 2019 Heavy alcohol use and compensated advanced alcohol related liver disease. 24 weeks intervention Unknown Active, not recruiting
 Profermin and probiotics
 NCT03863730
 Faecal microbiota transplant (FMT) [88-91] Restoration of gut symbiosis/correct dysbiosis. Multiple Open-label RCT’s 2017–2024 Multiple studies, variable protocols Higher short-term survival in SAH (at 1 and 3 months) compared to SOC FMT is promising for short-term benefits. Larger trials are awaited/not recommended.
Small sample size
Inclusion: SAH and moderate AH No survival advantage at 6 months to 1 year
 Rifaximin [95] Modulating intestinal microflora and influencing the gut-liver axis. Open-label Placebo controlled RCT 2025 SAH (MDF ≥32) No significant differences in 6-month LT-free survival or liver-related complications Failed/not recommended.
 NCT02485106 SOC (GC or pentoxifylline)×4 week: 29
SOC (GC or pentoxifylline)×4 week+rifaximin: 21
 Amoxicillin-clavulanate [96] Influencing systemic bacterial load Multicenter, double-blind RCT 2023 SAH: (MDF ≥32; MELD ≥21) and Biopsy proven No difference in 2-month survival but infection rates lower in amoxicillin-clavulanate group Failed/not recommended
 NCT02281929 SOC (GC)+placebo: 147
SOC (GC)+amoxicillinclavulanate: 145
Bile acid homeostasis modulation
 Obeticholic acid (OCA) [101] OCA is hypothesized to lessen liver exposure to toxic bile acids Phase 2a 2020 AAH (MELD: 11–20) The trial was prematurely terminated due to hepatotoxicity associated with OCA. Failed/not recommended.
 NCT02039219
 INT-787 [102] Selective FXR agonist Phase 2a 2025 SAH: MDF ≥32 and ≤70 or MELD≥18 and ≤25 Ongoing Awaited
 NCT05639543 Exact sample size unknown
Agents targeting modulation of specific signalling pathways
 Larsucosterol [105] Epigenetic modulator, improves cell survival Phase 2a 2025 SAH (MDF>32); 307 patients randomized. Both doses well tolerated. No 90-day mortality benefit overall but improved 90-day survival in USA cohort. Larger phase 3 trial required.
 NCT04563026 1:1:1 to LAR 30 mg LAR 90 mg or placebo.
Table 1. Prognostic scores commonly used for severe alcohol-associated hepatitis

GC, glucocorticoid; INR, international normalised ratio; MELD, model for end stage liver disease; PT, prothrombin time; SAH, severe alcohol-associated hepatitis; WBC, white blood cell.

Table 2. Alternative and emerging therapies for severe alcohol-associated hepatitis

AAH, alcohol-associated hepatitis; ALD, alcohol-associated liver disease; ELAD, extracorporeal liver assist device; FMT, faecal microbiota transplant; FXR, farnesoid X receptor; GC, glucocorticoid; G-CSF, granulocyte colony-stimulating factor; HRS, hepatorenal syndrome; IL-1β, interleukin-1 beta; IL-10, interleukin-10; MDF, Maddrey’s discriminant function; MELD, model for end-stage liver disease; NAC, N-acetylcysteine; OCA, obeticholic acid; RCT, randomized controlled trial; ROS, reactive oxygen species; SAH, severe alcoholassociated hepatitis; SOC, standard of care; TNF-α, tumor necrosis factor alpha; TLR-4, toll-like receptor-4.

Table 1.

Table 2.

Clin Mol Hepatol : Clinical and Molecular Hepatology
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