Hepatology (Baltimore, Md.) · 2026
Longitudinal assessment of the circulating cytokine profile of severe alcohol-associated hepatitis.
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Tornai David, Mitchell Mack C, McClain Craig J, Dasarathy Srinivasan, Barton Bruce, Szabo Gyongyi
Аннотация
BACKGROUND AND AIMS: Increased circulating pro-inflammatory cytokine levels correlate with mortality in severe alcohol-associated hepatitis (AH), but their kinetics during disease progression or response to treatment remain unexplored. We longitudinally assessed circulating biomarkers in a severe AH cohort enrolled in a multicenter, double-blind clinical trial.
APPROACH AND RESULTS: Eighty-nine patients with severe AH (MELD≥20) from 4 US sites were randomly assigned to treatment with IL-1 receptor antagonist (IL-1Ra) + pentoxifylline + zinc (anakinra: 47) or methylprednisolone + placebo (steroid: 42). Plasma levels of 43 indicators of AH pathology (inflammation, bacterial translocation, liver regeneration, tissue remodeling, and cell activation) were assessed on days 0, 7, 28, 90, and 180 after enrollment, and in 27 healthy controls. Baseline characteristics and cytokine levels were similar between treatment groups but significantly different compared with healthy controls. Consistent with anakinra administration, day 7 IL-1Ra levels were significantly increased in the anakinra group, accompanied by elevated levels of several other cytokines. IL-1β levels were increased in the steroid group on day 28. Strong correlations were observed between IL-1α and IL-17A, as well as IL-1β and IL-13, both before and during treatment. Although the dysregulated biomarkers demonstrated improving trends in survivors, most did not normalize by day 180. Markers associated with 90-day mortality were distinct between the treatment groups with few exceptions (IL-13-absolute level; sonic hedgehog and sTNF-R1-level change).
CONCLUSIONS: Circulating cytokine and immune biomarkers dynamically change in AH during treatment, disease progression, and/or resolution. Our results highlight the importance of treatment-specific biomarkers in future clinical trials.
APPROACH AND RESULTS: Eighty-nine patients with severe AH (MELD≥20) from 4 US sites were randomly assigned to treatment with IL-1 receptor antagonist (IL-1Ra) + pentoxifylline + zinc (anakinra: 47) or methylprednisolone + placebo (steroid: 42). Plasma levels of 43 indicators of AH pathology (inflammation, bacterial translocation, liver regeneration, tissue remodeling, and cell activation) were assessed on days 0, 7, 28, 90, and 180 after enrollment, and in 27 healthy controls. Baseline characteristics and cytokine levels were similar between treatment groups but significantly different compared with healthy controls. Consistent with anakinra administration, day 7 IL-1Ra levels were significantly increased in the anakinra group, accompanied by elevated levels of several other cytokines. IL-1β levels were increased in the steroid group on day 28. Strong correlations were observed between IL-1α and IL-17A, as well as IL-1β and IL-13, both before and during treatment. Although the dysregulated biomarkers demonstrated improving trends in survivors, most did not normalize by day 180. Markers associated with 90-day mortality were distinct between the treatment groups with few exceptions (IL-13-absolute level; sonic hedgehog and sTNF-R1-level change).
CONCLUSIONS: Circulating cytokine and immune biomarkers dynamically change in AH during treatment, disease progression, and/or resolution. Our results highlight the importance of treatment-specific biomarkers in future clinical trials.