The lack of reliable biomarkers capable of anticipating corticosteroid response remains one of the major challenges in the management of alcohol-associated hepatitis. In this setting, a team from the Sant Pau Research Institute (IR Sant Pau) has identified a specific profile of circulating plasma extracellular vesicles (EVs) associated both with treatment response and with medium- and long-term mortality. The study findings, published in the International Journal of Molecular Sciences, highlight the potential of these EVs as non-invasive biomarkers to improve prognostic stratification and support clinical decision-making in a disease associated with high mortality.
Alcohol-associated hepatitis is the most severe clinical manifestation of alcohol-related liver disease and is characterized by an intense systemic inflammatory response, immune dysfunction, and a high frequency of serious complications, including infections and acute kidney injury. Although corticosteroids are the only pharmacological treatment shown to improve short-term survival in selected patients, their benefit is limited, and their use increases the risk of infections, underscoring the need to identify early those patients who are most likely to benefit from treatment.
“In clinical practice, we still lack reliable tools that allow us to predict, before treatment initiation, which patients will respond to corticosteroids and which will experience unfavorable outcomes,” explains Dr. Edilmar Alvarado, researcher in the Digestive Pathology Group at IR Sant Pau and hepatologist at Sant Pau Hospital. “Our work addresses this clinical need through an integrative biological approach based on the analysis of circulating EVs.”
The study focused on the analysis of circulating plasma EVs in a prospective cohort of 46 patients with alcohol-associated hepatitis, compared with a control group of 28 healthy individuals. Samples were obtained during the first 24 hours of hospital admission and before corticosteroid treatment initiation, enabling assessment of the patients’ baseline biological status.
The research team characterized both the EV concentration and the surface antigen profile using advanced techniques capable of simultaneously analyzing markers related to the immune system, the endothelium, and other cellular compartments involved in disease pathophysiology.
The results show that patients with alcohol-associated hepatitis exhibit a significantly higher concentration of EVs compared with healthy controls, together with a profoundly altered surface antigen profile. In particular, enrichment of markers related to endothelial activation and immune dysfunction was observed, suggesting that these EVs integratively reflect the key pathogenic processes underlying the disease.
“EVs act as a biological fingerprint of the patient’s immune and endothelial status,” says Dr. Alvarado. “In alcohol-associated hepatitis, these alterations are directly linked to the development of serious clinical complications and to the patient’s subsequent clinical course.”
The study also identified specific associations between particular EV profiles and complications during hospitalization. Patients who developed infections displayed a profile compatible with adaptive immune system impairment, whereas those who developed acute kidney injury showed EVs enriched in endothelial and inflammatory activation markers, reinforcing the hypothesis of a liver-kidney axis mediated by vascular dysfunction.
One of the study’s most relevant findings was the identification of a specific EV pattern independently associated with corticosteroid treatment response. Responders exhibited higher levels of EVs enriched in markers related to endothelial integrity and cell migration, together with lower levels of inflammatory and platelet activation markers.
Based on these findings, the investigators developed a predictive model that demonstrated a high discriminatory capacity for identifying treatment responders, even after adjustment for relevant clinical variables such as age and sex, outperforming the classical clinical parameters commonly used in routine practice.
“These data indicate that corticosteroid response does not depend solely on initial clinical severity, but also on a specific biological state of the endothelium and immune system,” notes Dr. Alvarado. “Being able to identify this profile at hospital admission could help us make more precise therapeutic decisions and avoid potentially ineffective treatments.”
The study also analyzed medium- and long-term clinical outcomes. Patients who died or required liver transplantation during follow-up exhibited EVs enriched in endothelial activation and B-cell markers, together with a more severe inflammatory and hemodynamic profile.
The combination of these EV-derived markers with the MELD score significantly improved the predictive capacity for mortality compared with MELD alone, further supporting the potential clinical value of these EVs as a risk stratification tool in alcohol-associated hepatitis.
“Early identification of patients with a high probability of not responding to conventional medical treatment could facilitate earlier evaluation for liver transplantation and better clinical management planning,” concludes Dr. Alvarado. “Although these findings need to be validated in multicenter studies, they represent an important step toward more personalized medicine in a disease with a high mortality burden.”
Guinart-Cuadra A, Brujats A, Szafranska J, Guerrero R, Dinamarca F, Cantó E, Poca M, Román E, Sánchez-Ardid E, Fajardo J, Camps M, Mulet M, Soriano G, Escorsell À, Falcon-Perez JM, Gonzalez E, Ferrero-Gregori A, Gely C, Villalba J, Bataller R, Argemi J, Osuna-Gómez R, Vidal S, Alvarado-Tapias E. Immune and endothelial-related extracellular vesicles are associated with corticosteroid response and mortality in alcohol-associated hepatitis. Int J Mol Sci 2026;27:1258. https://doi.org/10.3390/ijms27031258
