Plasma Reticulocalbin 3 (RCN3) is a Novel Biomarker for the Early Diagnosis of Hepatopulmonary Syndrome in Cirrhotic Patients.

Background: Hepatopulmonary syndrome (HPS) is a severe complication in cirrhotic patients and characterized by abnormal intrapulmonary vasodilation (IPVD), resulting in impaired oxygenation. Recent studies highlight the pivotal role and clinical merit of Reticulocalbin 3 (RCN3) in interstitial pulmonary remodeling.

Objectives: This study aimed to investigate the clinical value of plasma RCN3 for early diagnosis of HPS in cirrhotic patients.

Methods: This prospective observational study on a cohort including 41 healthy control subjects and 247 cirrhotic patients with/without HPS, in which most HPS occurs in the mild stage. Plasma levels of RCN3 and key HPS-associated vasoactive factors are compared between patients with and without HPS/IPVD. The predictive value of RCN3 for the diagnosis of HPS is further analyzed.

Results: Patients with HPS had a severe condition. Plasma RCN3 was decreased in cirrhotic patients versus health control, but it is significantly higher in patients with HPS/IPVD than without non-HPS/IPVD. Notably, RCN3 level is positively correlated with P(A-a)O₂ and MELD scores as well as plasma levels of angiogenetic factors VEGF and AngII. Although the plasma levels of vasoactive factors were significantly different between HPS and non-HPS patients, only plasma RCN3 and albumin are independently associated with HPS in cirrhotic patients. Plasma RCN3 exhibits better predictive value in HPS diagnosis (RCN3, AUC = 0.657, 95% CI 0.571-0.744, p < 0.001). Interestingly, the combination of RCN3 and albumin achieves more efficiency in HPS prediction (AUC = 0.711, 95% CI 0.630-0.792, p < 0.0001).

Conclusions: Circulating RCN3 is likely a relatively specific earlier biomarker for the prediction of early or latent HPS in cirrhotic patients, and the combination of RCN3-ALB can achieve more efficiency in HPS prediction.