From rescue to recovery: Reframing severe alcoholic hepatitis management through 90-day survival

Abstract

Severe alcoholic hepatitis remains one of hepatology’s most urgent challenges, with rapid clinical deterioration and high early mortality. This manuscript comments on and contextualizes the recent systematic review by Quiñones-Calvo et al, which redirects attention from short-term endpoints toward 90-day survival, integrating evidence from associated clinical studies. For decades, corticosteroids have been the mainstay of treatment, reducing 28-day mortality but offering limited benefit for three months. The review emphasizes that the most critical threats to recovery, late infections, renal decline, and relapse, often emerge after the first month. By synthesizing recent studies, it highlights promising interventions such as fecal microbiota transplantation (FMT), which improved 90-day survival in a small randomized trial, and granulocyte colony-stimulating factor (G-CSF), which showed a robust survival benefit in a large retrospective cohort, alongside emerging strategies like plasma exchange and targeted biologics. These findings support a shift toward a two-phase care model: Early stabilization followed by recovery consolidation. For clinicians, such a model may help guide treatment decisions, with therapies like FMT or G-CSF warranting consideration in corticosteroid non-responders, pending further validation in larger randomized controlled trials. Adoption of 90-day survival as a central metric could bridge the gap between initial rescue and sustained remission, providing a more realistic measure of therapeutic success in one of hepatology’s most unforgiving conditions.

Key Words: Severe alcoholic hepatitis; Alcohol-associated hepatitis; Corticosteroids; 90-day survival; Fecal microbiota transplantation; Granulocyte colony-stimulating factor; Liver transplantation; Steroid non-response; Composite endpoints

Core Tip: Severe alcoholic hepatitis (SAH) is characterized by high short-term mortality, yet traditional 28-day endpoints overlook late complications that often determine recovery. This manuscript highlights a systematic review advocating 90-day survival as a more meaningful metric, capturing threats such as infections, renal decline, and relapse. Emerging therapies, fecal microbiota transplantation and granulocyte colony-stimulating factor, show potential in this extended window, particularly for corticosteroid non-responders. A proposed two-phase care model, early stabilization followed by recovery consolidation, may bridge the gap between initial rescue and sustained remission in SAH.

TO THE EDITOR

Among the liver disorders that test both our clinical skill and therapeutic optimism, severe alcoholic hepatitis (SAH) holds a singular position. SAH is typically defined by Maddrey’s discriminant function (≥ 32), model for end-stage liver disease (MELD) score (≥ 20), or the presence of clinical decompensation, and is distinct from milder forms of alcohol-associated hepatitis. Patients often present with rapidly progressive jaundice, coagulopathy, encephalopathy, and severe systemic inflammation, where each day without improvement can tip the balance toward death[1]. Over the last four decades, corticosteroids have remained the backbone of treatment, reducing 28-day mortality [e.g., odds ratio (OR) = 1.02, P = 0.87 in the STOPAH trial[2]] but failing to improve survival by the three-month mark[3]. The systematic review by Quiñones-Calvo et al[4] reframes this familiar landscape. Rather than accepting 28-day survival as the endpoint of therapeutic ambition, it challenges us to focus on 90-day survival, a metric that captures the critical window where late complications threaten recovery.

WHY 90-DAY SURVIVAL CHANGES THE CONVERSATION

The choice of 28-day survival as a primary endpoint in clinical trials has practical roots: It is easier to capture, less prone to confounding, and fits neatly within the budgetary and logistical constraints of most studies. However, it risks underestimating the complexity of SAH[3]. Between days 28 and 90, patients face a cascade of threats: (1) Late infections; (2) Renal deterioration; (3) Nutritional decline; and (4) The ever-present possibility of alcohol relapse. These events can undo early therapeutic success, as evidenced by the lack of 90-day mortality benefit with corticosteroids in large trials like STOPAH (OR = 1.02, P = 0.87)[5]. By shifting to 90-day survival, we acknowledge that the trajectory of SAH is shaped by processes, immune reconstitution, microbiome recovery, and hepatic regeneration, which take weeks to unfold. This shift, championed by Quiñones-Calvo et al[4], offers a more robust measure of therapeutic impact, urging clinicians and researchers to prioritize mid-term outcomes. In other words, the second month is not an afterthought; it is the proving ground for sustained recovery.

HIGHLIGHTS FROM THE REVIEW

In synthesizing evidence from recent studies, including those referenced here[1-3,5,6], the review identifies two particularly promising therapeutic directions[7-9]. The first is fecal microbiota transplantation (FMT), which targets the gut dysbiosis closely linked to SAH pathogenesis. By restoring microbial equilibrium, reducing systemic inflammation, and supporting hepatic repair, FMT offers a biological rationale for improving longer-term outcomes. A randomized controlled trial (RCT) from India (n = 26) reported a significant 90-day survival benefit with FMT [hazard ratio (HR) = 0.528, 95%CI: 0.279-0.998, P = 0.044][3], though limited by its small sample size. The second is granulocyte colony-stimulating factor (G-CSF), which mobilizes bone marrow-derived progenitor cells and enhances neutrophil function. This dual action may promote both liver regeneration and infection control, with a large retrospective cohort (n = 174) showing a robust survival benefit (HR = 0.38, 95%CI: 0.23-0.62, P < 0.01) compared to corticosteroids[10]. Other emerging interventions, such as plasma exchange and targeted biologics like anakinra, an interleukin-1 receptor antagonist, are still in exploratory phases but have shown inconsistent results. Notably, anakinra plus zinc yielded no significant benefit (HR = 0.69, P = 0.28)[6]. These findings contribute to a growing sense of therapeutic possibility, though Quiñones-Calvo et al[4] caution that heterogeneity in trial designs limits definitive conclusions. The key characteristics and 90-day outcomes of these selected studies are summarized in Table 1[2-9].

Table 1 Key studies on interventions in severe alcoholic hepatitis with reported 90-day outcomes, as discussed in the systematic review by Quiñones-Calvo et al[4].

Ref.	Country	Study design	Sample size (n)	Intervention	Key 90-day outcome
Philips et al[3], 2017	India	Pilot RCT	26	Fecal microbiota transplantation	Significantly improved survival (HR = 0.528, 95%CI: 0.279-0.998, P = 0.044)
Thursz et al[5], 2015	Multinational	RCT	1103	Prednisolone vs pentoxifylline vs placebo	No significant survival benefit for prednisolone
Louvet et al[2], 2018	Multinational	Meta-analysis of individual patient data	1103	Corticosteroids	Reduced 28-day mortality, but no significant 90-day benefit (odds ratio = 1.02)
Thompson et al[8], 2018	Multinational	RCT	203	Extracorporeal cellular therapy	No significant improvement in survival
Arab et al[9], 2021	Worldwide	Observational cohort study	1338	Timing of corticosteroid administration	Early steroid use (by day 3) is associated with optimized 90-day survival
Szabo et al[6], 2022	United States	RCT	200	Anakinra + zinc + pentoxifylline vs pentoxifylline	No significant survival benefit (HR = 0.69, P = 0.28)
Louvet et al[7], 2023	France	RCT	284	Prophylactic antibiotics	No significant reduction in 90-day mortality

HR: Hazard ratio; RCT: Randomized controlled trial.

STRENGTHS AND LIMITATIONS

The greatest strength of the review lies in its deliberate choice of 90-day survival as a unifying metric, focusing attention on a clinically relevant but underexplored period in SAH care. It compels both researchers and clinicians to rethink how we define success. Still, the evidence base is far from definitive. The included trials vary in design, sample size, patient selection criteria, and co-interventions. For example, only three of the eight studies assessed 90-day mortality, while five focused on survival, with inconsistent reporting of primary vs secondary outcomes[4]. Many are underpowered to detect modest but meaningful differences at 90 days, and several rely on open-label designs vulnerable to bias. These limitations underscore the need for large, rigorously conducted, multicenter randomized trials before integrating these interventions into standard protocols. Quiñones-Calvo et al’s qualitative synthesis[4], necessitated by this heterogeneity, highlights the urgency of standardized trial designs to validate promising therapies like FMT and G-CSF.

Beyond these strengths, important limitations must be acknowledged. Many of the available studies are small and underpowered, often conducted in single centers with limited generalizability. Open-label designs raise the risk of bias, and inconsistent endpoint definitions complicate comparison. For example, only three of the eight studies reported 90-day mortality as a primary endpoint, while others considered it secondary or exploratory. Lack of blinding and heterogeneity in inclusion criteria (e.g., Maddrey vs MELD thresholds) further constrain interpretability. These limitations highlight that current findings should be viewed as hypothesis-generating, pending validation in large, multicenter, rigorously blinded RCTs.

CLINICAL AND RESEARCH IMPLICATIONS

If validated, these novel approaches could lead to a two-phase model of SAH care. The first phase would focus on early stabilization, using corticosteroids or alternative anti-inflammatory strategies to blunt the initial cytokine storm. The second phase would consolidate recovery by deploying microbiome restoration, immune modulation, and regenerative therapies to maintain clinical momentum and prevent late deterioration. For practicing gastroenterologists, this model could guide treatment decisions, prioritizing therapies like G-CSF or FMT in corticosteroid non-responders, pending further validation[1,2,4]. This approach echoes treatment paradigms in other acute-on-chronic conditions, such as acute coronary syndrome and septic shock, where initial rescue is followed by targeted consolidation therapy[3]. The review’s emphasis on 90-day survival underscores the need for clinical trials to test this model, ensuring therapies address both short-term crises and mid-term recovery[4].

THE MISSING PIECE: LIVER TRANSPLANTATION IN SAH

The systematic review by Quiñones-Calvo et al[4] highlights a striking gap: No eligible studies assessed 90-day survival or mortality post-liver transplantation (LT) in SAH, despite LT’s established role in improving long-term outcomes for carefully selected corticosteroid non-responders[3]. Key studies have demonstrated the efficacy of early LT. Mathurin et al[11] conducted a landmark study showing that carefully selected patients with a first episode of SAH not responding to medical therapy who underwent early LT had a significantly improved 6-month survival compared to matched controls (77% vs 23%, P < 0.001)[11]. Similarly, a subsequent multicenter United States study by Lee et al[12] reported that early LT conferred a 1-year survival of 94% at 180 days and 84% at 1 year, with benefit observed even in patients who did not achieve 6 months of pre-transplant abstinence.

However, the impact of LT specifically on 90-day survival remains less well documented, as most studies have focused on 6-month and 1-year horizons. Given that early post-transplant mortality is most strongly influenced by infection, surgical complications, and relapse, dedicated studies evaluating 90-day outcomes are urgently needed to allow direct comparison with emerging medical therapies. Ethical and logistical complexities remain central: Organ scarcity, the need for rigorous multidisciplinary psychosocial assessment, and concerns about alcohol relapse risk must be carefully weighed against the clear survival benefit in appropriate candidates.

Future studies should incorporate 90-day endpoints to better contextualize LT alongside pharmacologic and biologic interventions. This would allow a more balanced comparison of therapeutic strategies and align LT evaluation with the broader framework of recovery consolidation in SAH, as championed by Quiñones-Calvo et al[4].

Part of the reason for this gap is methodological. Most LT studies in SAH have emphasized long-term survival (1-5 years), graft function, and relapse rates, with limited attention to early post-transplant mortality. Small cohort sizes and ethical concerns about randomization also constrain prospective data collection. To improve this area, future efforts should focus on multicenter registries with standardized reporting of 90-day outcomes, prospective trials incorporating relapse risk assessment, and comparative analyses of LT vs medical therapies. Such measures would clarify the short-term to mid-term role of LT in SAH and allow a more balanced appraisal of its benefits and limitations.

FUTURE PRIORITIES

In addition to advancing diagnosis and treatment, prevention must remain central to any comprehensive strategy for SAH. Primary prevention includes population-level policies such as alcohol taxation, advertising restrictions, and early screening programs. Secondary prevention targets individuals with harmful drinking patterns, emphasizing timely referral to addiction treatment and psychosocial support. Tertiary prevention involves optimizing nutrition, correcting micronutrient deficiencies (e.g., zinc, vitamin D), and managing comorbidities that exacerbate hepatic injury. Integrating preventive measures with therapeutic innovation will help reduce the incidence of SAH and improve long-term outcomes[1].

Progress in this field will require biomarker-guided stratification to identify immune, inflammatory, or microbiome profiles predictive of response to specific interventions. Composite endpoints that integrate mortality with liver function recovery, infection rates, and patient-reported outcomes will provide a more holistic assessment of benefit. The absence of studies evaluating 90-day survival post-LT, as noted by Quiñones-Calvo et al[4], highlights a critical research gap, given LT’s role in selected SAH patients. Multidisciplinary trial designs that combine hepatology, infectious diseases, microbiology, and addiction medicine expertise will be essential, as will international collaboration to capture diverse patient populations and enhance generalizability. These efforts should prioritize standardized protocols to overcome the heterogeneity that limited the review’s ability to perform a meta-analysis[4].

CONCLUSION

The journey from day 1 to day 90 in SAH is perilous yet represents a critical therapeutic window. By embracing 90-day survival as a central endpoint, we challenge ourselves to think beyond short-term rescue and toward durable recovery. The systematic review by Quiñones-Calvo et al[4] is more than a summary of emerging therapies like FMT and G-CSF, it is a call to shift our collective ambition. By adopting a two-phase care model, early stabilization followed by recovery consolidation, we can transform outcomes, bridging the gap between initial survival and lasting remission for one of hepatology’s most unforgiving conditions.