Artru Florent, Atkinson Stephen, Trovato Francesca, Tyson Luke D, Patel Vishal C, Vergis Nikhil, Kano Noora, Goldin Robert, Quaglia Alberto, Pechlivanis Alexandros, Morgan Phillip, Mujib Salma, Cavazza Anna, Jerome Ellen, Zentar Marc, Sheth Roosey, Morrison Maura, Triantafyllou Evangelos, Holmes Elaine, Gómez-Romero María, McPhail Mark J, Thursz Mark
Institute of Liver Studies, King's College Hospital London, London, UK.
Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.
JHEP Rep. 2025 Mar 1;7(6):101367. doi: 10.1016/j.jhepr.2025.101367. eCollection 2025 Jun.
BACKGROUND & AIMS: Severe alcohol-related hepatitis (sAH) is an inflammatory condition with high short-term mortality. Hypothesis-driven approaches have failed to identify effective treatments. Given the role of lipids as inflammatory mediators, this study aimed to identify lipidomic changes and lipid species associated with sAH and mortality risk.
Untargeted lipidomics was performed on serum samples from two cohorts of patients with sAH and decompensated cirrhosis (DC). Principal component analysis and orthogonal partial least squares discriminant analysis were used to assess lipidome changes. Correlations were made with lipoproteins, lipid mediators, cytokines, cytokeratin fragments, and histological indices.
In the first part, 78 patients with sAH were matched on bilirubin levels with 23 patients with DC. Lipidomics identified a distinct sAH signature involving glycerophospholipids, including PC(34:2) (odds ratio [OR] 2.18, 95% confidence interval [CI] 1.45-7.05, = 0.01), PC(O-38:5) (OR 3.31, 95% CI 2.23-7.14, = 0.002), PI(38:4) (OR 0.71, 95% CI 0.46-0.88, = 0.02), and LPC(18:1) (OR 0.47, 95% CI 0.32-0.82, = 0.01). These lipids demonstrated excellent discriminatory power between sAH and DC with areas under the receiver operating characteristic curve (AUROCs) between 0.87 and 0.88. In the second part, in 159 sAH patients, specific lipids, including carnitines CAR(2:0) (OR 2.51, 95% CI 1.25-4.96, = 0.008) and CAR(16:1) (OR 2.21, 95% CI 1.09-7.48, = 0.009), were linked to 90-day mortality. Acylcarnitines correlated with disease severity parameters such as model for end-stage liver disease, pro-inflammatory cytokines levels, and hepatocyte ballooning on pathology.
Untargeted lipidomics identified a glycerophospholipid and sphingolipid signature distinguishing sAH from DC, implicating lipid species involved in liver regeneration and immune function. Acylcarnitine accumulation in patients with sAH and poor prognosis suggests mitochondrial dysfunction and warrants further investigation into therapeutic potential.
Lipids can act as mediators at the interface between the immune system and metabolism, potentially contributing to the pathogenesis and outcomes of patients with severe alcohol-related hepatitis, prompting us to investigate lipidomic changes in this population using untargeted approaches, compared with patients with decompensated cirrhosis. This study highlights a distinct lipidomic signature in patients with severe alcohol-related hepatitis compared with decompensated cirrhosis, primarily involving glycerophospholipids and sphingolipids. Specific lipid classes, such as acylcarnitines, suggest significant mitochondrial dysfunction and are associated with disease severity and short-term mortality in patients with severe alcohol-related hepatitis. These findings underscore the importance of targeted investigations into these lipid species, their pathways, and their links to disease severity and outcomes, particularly in this condition that currently lacks specific treatments.
严重酒精性肝炎（sAH）是一种短期死亡率很高的炎症性疾病。基于假设的方法未能找到有效的治疗方法。鉴于脂质作为炎症介质的作用，本研究旨在确定与sAH及死亡风险相关的脂质组变化和脂质种类。
对两组sAH和失代偿期肝硬化（DC）患者的血清样本进行非靶向脂质组学分析。采用主成分分析和正交偏最小二乘法判别分析评估脂质组变化。将其与脂蛋白、脂质介质、细胞因子、细胞角蛋白片段和组织学指标进行相关性分析。
在第一部分中，78例sAH患者与23例DC患者按胆红素水平进行匹配。脂质组学确定了一种独特的sAH特征，涉及甘油磷脂，包括PC(34:2)（比值比[OR]2.18，95%置信区间[CI]1.45 - 7.05，P = 0.01）、PC(O - 38:5)（OR 3.31，95% CI 2.23 - 7.14，P = 0.002）、PI(38:4)（OR 0.71，95% CI 0.46 - 0.88，P = 0.02）和LPC(18:1)（OR 0.47，95% CI 0.32 - 0.82，P = 0.01）。这些脂质在sAH和DC之间显示出优异的鉴别能力，受试者工作特征曲线下面积（AUROCs）在0.87至0.88之间。在第二部分中，在159例sAH患者中，特定脂质，包括肉碱CAR(2:0)（OR 2.51，95% CI 1.25 - 4.96，P = 0.008）和CAR(16:
