By Eugenia Tsai, MD
A recent Nature Communications study by Kalsotra and colleagues offers new molecular insight into why patients with alcohol-associated liver disease (ALD)—particularly those with severe alcohol-associated hepatitis (sAH)—often fail to regain hepatic function despite abstaining from alcohol. The investigators found that dysregulation of RNA-splicing machinery disrupts hepatocyte proliferation and contributes to regenerative failure.
In healthy regeneration, hepatocytes briefly enter a fetal-like progenitor state before maturing back into functional cells. In ALD, this process stalls. Hepatocytes remain trapped in a nonfunctional, “quasi-progenitor” state that cannot restore liver function or repopulate damaged tissue.
To explore the clinical implications of these findings, Medscapecontributor Eugenia Tsai, MD, spoke with Jan Petrasek, MD, PhD, an expert in transplant hepatology and alcohol-associated liver disease at the Texas Liver Institute. Petrasek is also an adjunct associate professor at the University of Texas Health Sciences in San Antonio.
Persistent Dysfunction After Abstinence
The study suggests that hepatocytes in ALD can become “stuck” in a transitional state, unable to regenerate even after alcohol cessation. How do you interpret this regenerative arrest, and what does it mean for transplant timing and prognosis?
In a healthy liver subjected to acute injury, hepatocytes can transiently de-differentiate, proliferate, and then re-differentiate into mature, functioning hepatocytes. In ALD and sAH, hepatocytes enter that initial transitional/fetal-like state but do not complete the maturation step. Instead of repopulating functional parenchyma, they remain metabolically inefficient and synthetically weak (the “stuck” state).
Functionally, in patients with sAH, that looks like persistent hyperbilirubinemia, coagulopathy, and low albumin despite removal of the inciting toxin (ie, alcohol). Clinically, this matches well-described observations: in sAH, a substantial fraction of patients who are still decompensated at 2-4 weeks of abstinence never meaningfully recover hepatic function even at 90 or 180 days.
The concept of early liver transplant for sAH was justified on exactly this basis: mortality at 28 days is about 30%-40%, and at 6 months approximately 60%-70% in nonresponders to medical therapy, despite enforced abstinence in the hospital. In these cases, the liver is not “slowly getting better”; it is failing to regenerate.
This process of regenerative arrest helps explain why some patients do not improve even with abstinence and time. Practically, if a patient with sAH remains deeply jaundiced, encephalopathic, and coagulopathic after the first 1-2 weeks of maximal supportive care, the barrier is not only inflammation or cholestasis; instead, the liver may no longer be capable of meaningful autologous recovery. Prolonged abstinence alone is unlikely to restore normal function in that trajectory.
This argues against waiting months “to see if sobriety helps” in patients with sAH already in acute-on-chronic liver failure physiology. Instead, once it is clear over the first several weeks that bilirubin, international normalized ratio (INR), renal function, and encephalopathy are not improving, these patients should already be moving through an early liver transplant pathway rather than a “watchful waiting” pathway.
Inflammation and Failed Regeneration
Inflammation appears to suppress ESRP2, a key splicing regulator. Could anti-inflammatory strategies improve regenerative capacity?
Inflammation contributes to the regenerative failure in ALD, but it is one part of a multifactorial process. In the Nature Communications study, inflammation correlated with down-regulation of several splicing regulators — including, but not limited to, epithelial splicing regulatory protein 2 (ESRP2) — and with up-regulation of inhibitory heterogeneous ribonucleoproteins (hnRNPs). These changes impair accurate RNA transcript processing required for hepatocyte proliferation and redifferentiation.
Clinically, inflammation in sAH is both a symptom and driver of injury. Cytokines such as TNF-alpha, IL-1 beta, and IL-6 activate stress-response pathways that further destabilize the spliceosome and compromise mitochondrial and metabolic recovery. Yet, experimental data suggest that splicing abnormalities persist even when inflammation subsides, implying that the damage is partly “imprinted” through mechanisms such as oxidative stress and epigenetic remodeling.
While anti-inflammatory therapy may relieve part of the regenerative block, it is unlikely to fully restore function once splicing machinery and metabolic networks are deranged. Steroids might transiently blunt the inflammatory components of liver injury, but the long-term regenerative deficit likely requires broader correction of hepatocyte homeostasis — through metabolic support, suppression of oxidative stress, and potentially future splicing-targeted therapies. Thus, inflammation is a modifiable contributor, but not a curative target, in restoring hepatic regeneration after alcohol-induced injury.
RNA Splicing Factors as Clinical Biomarkers
Could splicing-related factors like ESRP2 evolve into biomarkers to guide prognosis or therapy selection?
It is best to think of ESRP2 not as a stand-alone biomarker, but as one illustrative example of a much broader dysregulation of the splicing network. The prognostic signal comes from the overall pattern of spliceosome dysfunction rather than from a single gene.
The study found that reduced expression of multiple core splicing factors (SF3B1, U2AF2, and SRSF proteins) and increased splicing repressors (hnRNP family) correlated with worse histologic recovery and clinical outcomes in alcoholic hepatitis. ESRP2 simply exemplifies how epithelial splicing programs are lost when hepatocytes become “stuck” in a fetal-like state, but it is not yet validated as an independent clinical marker.
For clinicians, the practical takeaway is that splicing-related signatures could eventually refine prognostication beyond current models (eg, Model for End-Stage Liver Disease, Lille Model for Alcoholic Hepatitis, or the Glasgow score). If validated, panels assessing global splicing imbalance or transcriptomic de-differentiation might help identify patients whose hepatocytes have lost regenerative competence despite abstinence.
For now, the best surrogate for that biology remains clinical trajectory: lack of improvement in bilirubin, INR, and renal function within the first several weeks of abstinence or corticosteroid therapy reliably predicts nonrecovery and should prompt early transplant evaluation rather than prolonged observation.
Supporting Regeneration in Clinical Practice
While molecular therapies evolve, what can clinicians do to optimize hepatic recovery?
Although no therapy yet restores normal RNA splicing, clinicians can optimize the physiologic environment for hepatic recovery. The pillars of care in sAH are injury minimization, metabolic support, and infection prevention.
Early and sustained nutritional therapy remains one of the few interventions shown to improve survival. Target 1.2-1.5 g/kg/day of protein and 30-40 kcal/kg/day of total calories, prioritizing enteral nutrition when feasible. Correction of micronutrient deficiencies — particularly thiamine, folate, zinc, and vitamin D — supports mitochondrial and nucleic acid metabolism.
Inflammation control remains essential but nuanced. Corticosteroids should be reserved for carefully selected patients and used to blunt short-term inflammatory injury, not to reverse regeneration failure. Beyond drugs, avoiding iatrogenic insults (eg, nephrotoxins, sedatives) and controlling sepsis are key, as systemic inflammation perpetuates hepatic stress.
Infectious surveillance is absolutely critical, as sAH represents a paradoxical state of hyperinflammation in the liver coupled with profound systemic immunosuppression.
Preventing sarcopenia through early mobilization, maintaining euvolemia, and optimizing glycemic control also preserves regenerative signaling. If hepatic indices plateau or worsen after 2-4 weeks of abstinence, this typically reflects irreversible regenerative arrest and warrants timely transplant referral.
Reference: https://www.medscape.com/viewarticle/why-some-livers-cant-recover-after-alcohol-abstinence-2025a1000wji?form=fpf
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