Current insights into pathogenesis and anti-inflammatory treatment strategies for severe alcohol-associated hepatitis: focus on neutrophil-targeted therapies

Abstract

Alcohol-associated hepatitis (AH) is the leading cause of liver-related mortality, with severe alcohol-associated hepatitis (SAH) showing a short-term mortality rate of 20%–50% even in developed countries. Corticosteroids are the only evidence-based pharmacologic treatment, but their efficacy is limited to short-term survival, with 30%–40% of patients achieving a complete response. Early liver transplantation (LT) has been explored as a salvage therapy for steroid-refractory SAH, but its feasibility is restricted by ethical concerns and donor shortages, particularly in Japan. In the absence of LT eligibility, patients are often left with the best supportive care, underscoring the urgent need for alternative salvage therapies. Recent studies have explored selective anti-inflammatory strategies targeting proinflammatory cytokines, such as TNFα and IL-1β. However, clinical trials have yet to demonstrate sufficient efficacy to outweigh the increased risk of infection. Granulocyte colony-stimulating factor (G-CSF) therapy has been investigated for its potential to promote liver regeneration, but its efficacy remains inconsistent across populations. Neutrophil-targeted therapies, including granulocyte-monocyte/macrophage apheresis (GMA), have emerged as a novel approach. Our recent pilot study demonstrated improved survival in patients with steroid-refractory SAH treated with GMA, supporting its potential as a safe and effective anti-inflammatory therapy. This review summarizes the latest advances in the treatment of SAH and emphasizes the need for novel salvage therapies to address unmet needs in steroid-refractory cases. Further research is essential to validate these new therapies and to optimize treatment strategies to improve the long-term prognosis of SAH.