Di Zeo-Sánchez Daniel E, Díaz-Alberola Irene, Pinazo-Bandera José María, García-Cortés Miren, Sanabria-Cabrera Judith, Robles-Díaz Mercedes, Álvarez-Álvarez Ismael, Lucena M Isabel, Andrade Raúl J, Villanueva-Paz Marina, Stephens Camilla
UGC Aparato Digestivo, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain.
Centro de investigación en red en el área temática de enfermedades hepáticas y digestivas (CIBERehd), Madrid, Spain.
Br J Pharmacol. 2025 Jun 25. doi: 10.1111/bph.70123.
Adverse immuno-inflammatory responses possibly influenced by bacterial compounds reaching the liver as a consequence of altered intestinal permeability appear to be crucial in the pathogenesis of drug-induced liver injury and steatotic liver diseases. This study aimed to assess intestinal permeability and immuno-inflammatory status in patients by measuring indirect biomarkers.
Circulating marker levels were measured in serum and plasma samples of 36 healthy controls, 32 patients with drug-induced liver injury, 14 with autoimmune hepatitis, 13 with viral hepatitis, 40 with metabolic dysfunction-associated steatotic liver disease (MASLD) and 16 with drug-induced steatosis. All patients with acute liver injury were identified (visit 1) and followed for >30 days (visit 2). Correlation analyses were performed to determine potential associations.
Drug-induced liver injury, autoimmune hepatitis and viral hepatitis patients had higher levels of LBP, CD14, CD163, MCSF-1R (CSFR) and ICAM-1 and significantly lower levels of MAdCAM-1 and zonulin at detection of liver injury compared with healthy controls or the second visit. Drug-induced steatosis and MASLD patients had increased levels of S100A9, S100A12 and zonulin. MASLD patients with significant fibrosis (F2-F4) also had higher levels of CD163 and MCSF-1R. No difference was found between drug-induced steatosis and MASLD with no or low fibrosis.
Our results highlight similarities in macrophage activation, intestinal barrier dysfunction and translocation of bacterial products in liver injury of various aetiologies. A better understanding of the pathophysiological mechanisms may aid the development of targeted therapies for liver inflammation and fibrosis.
由于肠道通透性改变，细菌成分进入肝脏可能会引发不良免疫炎症反应，这在药物性肝损伤和脂肪性肝病的发病机制中似乎起着关键作用。本研究旨在通过测量间接生物标志物来评估患者的肠道通透性和免疫炎症状态。
检测了36名健康对照者、32名药物性肝损伤患者、14名自身免疫性肝炎患者、13名病毒性肝炎患者、40名代谢功能障碍相关脂肪性肝病（MASLD）患者和16名药物性脂肪变性患者的血清和血浆样本中的循环标志物水平。所有急性肝损伤患者均被确诊（首次就诊）并随访超过30天（第二次就诊）。进行相关性分析以确定潜在关联。
与健康对照者或第二次就诊时相比，药物性肝损伤、自身免疫性肝炎和病毒性肝炎患者在肝损伤检测时LBP、CD14、CD163、MCSF-1R（CSFR）和ICAM-1水平较高，而MAdCAM-1和闭合蛋白水平显著较低。药物性脂肪变性和MASLD患者的S100A9、S100A12和闭合蛋白水平升高。有显著纤维化（F2-F4）的MASLD患者的CD163和MCSF-1R水平也较高。在无纤维化或低纤维化的药物性脂肪变性和MASLD患者之间未发现差异。
我们的数据突出了不同病因所致肝损伤中巨噬细胞激活、肠道屏障功能障碍和细菌产物易位的相似性。更好地理解病理生理机制可能有助于开发针对肝脏炎症和纤维化的靶向治疗方法。
