Leucine-rich alpha-2 glycoprotein reflects transmural inflammation assessed by through-the-scope endoscopic ultrasonography: A prospective study in small-bowel Crohn’s disease

Abstract

BACKGROUND

Assessment of transmural inflammation in small-bowel Crohn’s disease (CD) remains challenging. Although serum leucine-rich alpha-2 glycoprotein (LRG) has shown potential for evaluating transmural disease activity in CD, its association with small-bowel transmural inflammation remains unclear.

AIM

To evaluate the association between serum LRG levels and transmural inflammation assessed by through-the-scope endoscopic ultrasonography during double-balloon enteroscopy (DBE-EUS).

METHODS

This prospective single-center diagnostic study enrolled 132 consecutive patients with small-bowel CD between January 2022 and March 2025. All participants underwent baseline assessment, including LRG measurement and DBE-EUS examination, and were subsequently followed longitudinally for exploratory evaluation of clinical outcomes. Serum LRG levels were measured by enzyme-linked immunosorbent assay. DBE-EUS was performed using a through-the-scope miniprobe ultrasound system, and EUS parameters were assessed. Transmural inflammation was defined according to two separate criteria, namely a total wall thickness (TWT) ≥ 2.65 mm and a submucosal thickness (SMT) ≥ 0.95 mm, based on previously established cutoff values.

RESULTS

Serum LRG levels were significantly higher in patients with transmural inflammation than in those with transmural healing and showed strong positive correlations with DBE-EUS parameters, particularly TWT (r = 0.664) and SMT (r = 0.642). For detecting transmural inflammation defined by TWT ≥ 2.65 mm, LRG demonstrated an area under the curve (AUC) of 0.875 [95% confidence interval (CI): 0.816-0.935], which was higher than that of C-reactive protein (CRP) (AUC = 0.732; 95%CI: 0.641-0.822) and comparable to fecal calprotectin (FC) (AUC = 0.847; 95%CI: 0.780-0.913). For SMT ≥ 0.95 mm, LRG achieved an AUC of 0.833 (95%CI: 0.764-0.902), comparable to FC (AUC = 0.837; 95%CI: 0.766-0.908) and higher than that of CRP (AUC = 0.720; 95%CI: 0.631-0.810). Similar diagnostic performance was observed among patients in clinical remission, with LRG showing AUCs of 0.871 (95%CI: 0.794-0.948) for TWT ≥ 2.65 mm and 0.875 (95%CI: 0.790-0.960) for SMT ≥ 0.95 mm. In the exploratory prognostic analyses, elevated serum LRG levels and DBE-EUS evidence of persistent transmural inflammation were associated with an increased risk of hospitalization, whereas neither parameter significantly predicted clinical relapse in patients who had achieved clinical remission.

CONCLUSION

Serum LRG levels are significantly associated with transmural inflammation in small-bowel CD as assessed by DBE-EUS. LRG may serve as a reliable and noninvasive biomarker for evaluating transmural disease activity in small-bowel CD.

Keywords: Crohn’s disease; Leucine-rich alpha-2 glycoprotein; Endosonography; Transmural inflammation; Diagnostic accuracy

Core Tip: This prospective study investigated the association between serum leucine-rich alpha-2 glycoprotein (LRG) levels and transmural inflammatory activity in patients with isolated small-bowel Crohn’s disease (CD) using endoscopic ultrasonography during double-balloon enteroscopy (DBE-EUS). Serum LRG levels were strongly correlated with DBE-EUS-derived measures of transmural inflammation and demonstrated diagnostic performance comparable to fecal calprotectin and superior to C-reactive protein. Elevated LRG levels were also associated with an increased risk of CD-related rehospitalization, supporting LRG as a promising noninvasive biomarker for evaluating transmural disease activity in small-bowel CD.