Reticuloendothelial activation and phenotypic alteration of peripheral monocytes with enhanced liver recruitment drive liver injury secondary to yellow phosphorus.

Abstract

Monocytes and macrophages play a crucial role in the pathogenesis of acute liver failure (ALF). We aimed to study reticuloendothelial activation and its correlation with disease severity in commonly encountered yellow phosphorus (rodenticide)-induced hepatotoxicity patients. We also studied peripheral monocyte phenotype in a subset of patients. Reticuloendothelial activation markers were analyzed and correlated with disease severity score in a prospectively collected database of yellow phosphorus-related hepatoxicity patients between 2018 and 2021. In a prospective cohort of these patients and age-matched healthy controls, peripheral blood monocyte phenotyping was performed. Reticuloendothelial activation markers were analyzed in 67 patients [Age: 23(12-64) years; median (range), men: 25, acute liver injury (ALI): 38, ALF: 29, model for end-stage liver disease (MELD) score: 28 (7-40)] of yellow phosphorus-induced hepatotoxicity. Serum ferritin (927; 10.3-34807ng/mL), sCD163 (4.59; 0.11-12.7μg/mL), sCD25 (3050; 5.6-17300pg/mL) and plasma von Willebrand factor (423.5, 103-1106IU/dL) were increased and showed significant correlation with liver disease severity assessed by MELD score (ρ=0.29, ρ=0.6, ρ=0.56 and ρ=0.46 respectively). Phenotyping and serum immune markers were performed in seven patients (M: 4; age: 27, 15-37years; median, range; MELD score: 36, 21-40) and compared with eight healthy controls. Increase in classical monocytes and decrease in patrolling and intermediate monocyte subsets were observed in ALF cohort. HLA-DRlow CD163hi (immune exhaustion), CD64hi (immune complex-mediated response), and CCR2hi (liver homing) monocyte phenotype was noted. Altered peripheral monocyte phenotype with enhanced liver homing and macrophage activation, suggests important role of innate immune activation, and provides a potential therapeutic target, in yellow phosphorus-induced hepatotoxicity.