Alcohol‐Induced ICAM‐1 And VCAM‐1 Promote Hepatic Leukocyte Infiltration And Are Biomarkers For Mortality Prediction In Alcohol‐Associated Hepatitis

Purpose/Background Alcohol‐associated hepatitis (AH) characterized by high morbidity and mortality is a severe inflammatory liver disease with no FDA approved therapies. Accurate biomarkers are needed to predict mortality and therapy outcomes. Alcohol‐induced immune cell activation, elevated cytokines and hepatic leukocyte infiltration leading to persistent hepatic inflammation are hallmarks of AH. Soluble vascular and intercellular cell adhesion molecules (sVCAM‐1 and sICAM‐1) that promote leukocyte infiltration are considered biomarkers of endothelial activation/dysfunction. In this study, we examined the association between endothelial activation markers and proinflammatory cytokines/chemokines, as well as hepatic leukocyte infiltration and mortality prognosis in AH patients. Methods Plasma samples were collected from 54 AH patients, 16 alcohol use disorder (AUD, no liver disease) and 16 healthy controls. Multiplex immunoassays were used to measure soluble ICAM‐1, VCAM‐1, cytokines and chemokines. Data were analyzed by ROC (receiver operating characteristics) curves, Kaplan‐Meier and Cox regression analyses. Immunofluorescence staining of liver sections was used to determine ICAM‐1 and VCAM‐1 levels and assess hepatic leukocyte infiltration. Data Higher plasma levels of the endothelial activation markers sICAM‐1 and sVCAM‐1 were detected in AH patients along with higher cytokines/chemokines (IL‐1β, TNFα, IL‐6, IL‐8, MCP1α and MIP1α). Elevated sICAM‐1 and sVCAM‐1 in AH patients showed a significant positive correlation with clinical prognostic/severity indicators MELD, Maddrey's Discriminant Function, and Childs‐Pugh scores. Notably, sICAM‐1 and sVCAM‐1 were significantly elevated in the non‐survivors compared to survivors, concurrent with increased in hepatic infiltration of leukocytes (neutrophils, CD8 + and NKT cells) and cell death. Moreover, survival analysis showed that sICAM‐1 and sVCAM‐1 were good predictors for mortality in AH. Results and Conclusions Our study emphasizes that endothelial activation markers sICAM‐1 and sVCAM‐1 may serve as biomarkers for the assessment of disease severity, progression and prediction of mortality. sICAM‐1 and sVCAM‐1 could be potential therapeutic targets for prevention of hepatic leukocyte infiltration in AH.