Evaluation of Serum Leucine-Rich Alpha-2 Glycoprotein as a New Inflammatory Biomarker of Inflammatory Bowel Disease

Abstract

Studies on serum leucine-rich alpha-2 glycoprotein (LRG) in inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are scarce; the methods for estimating disease activity are less established, particularly for CD. This study is aimed at evaluating the utility of serum LRG as a potential inflammatory marker for IBD and to investigate the LRG gene expression in peripheral blood mononuclear cells (PBMCs) as a possible source of serum LRG. Overall, 98 patients with UC and 96 patients with CD were prospectively enrolled and clinically evaluated; 92 age-matched individuals served as the healthy controls. The blood samples were analyzed for serum LRG levels and routine laboratory parameters. Disease activity was assessed clinically and endoscopically. Finally, LRG gene expression in the PBMCs from a different cohort (41 patients with UC, 34 patients with CD, and 30 healthy controls) was examined. The serum LRG levels were higher during active disease than during inactive disease; additionally, serum LRG levels were positively correlated with clinical disease activity, C-reactive protein (CRP) levels, and other laboratory parameters in patients with UC and CD and with endoscopic disease activity in UC. UC and CD showed comparable areas under the curve (AUC) values for determining clinical remission and differentiating between endoscopic remission associated with LRG and CRP. The levels of LRG mRNA were also increased in PBMCs from patients with UC and CD and reflected disease activity. These data suggest that serum LRG, originated partially from PBMCs, is an inflammatory marker in UC and CD. A large-scale well-designed study should be conducted in the future to more accurately reveal the clinical significance of LRG in patients with IBD.

Figure 1

Serum levels of leucine-rich alpha-2 glycoprotein (LRG) in patients with ulcerative colitis, patients with Crohn's disease, and healthy control individuals. The bars indicate the median ± 25^th percentile. The lower bar indicates the 10^th percentile, and the upper bar indicates the 90^th percentile.

Figure 2

Comparison of the serum leucine-rich alpha-2 glycoprotein (LRG) levels between active and inactive disease, according to the involved area in patients with ulcerative colitis (a) and Crohn's disease (b). The bars indicate the median ± 25^th percentile. The lower bar indicates the 10^th percentile, and the upper bar indicates the 90^th percentile. I: inactive; A: active; n.s.: not significant.

Figure 3

Efficacy of the serum leucine-rich alpha-2 glycoprotein (LRG) level as a biomarker for ulcerative colitis, assessed using the partial Mayo score (PMS), (a) and for Crohn's disease assessed using the Harvey-Bradshaw index (HBI) (b). Receiver operating characteristic (ROC) curves for the serum LRG and C-reactive protein (CRP) levels, as evaluated according to the MS in ulcerative colitis (c) and the HBI in Crohn's disease (d). Values of the area under the ROC curve (AUC) are shown. Clinical remission was defined as MS ≤ 2 in UC and HBI < 5 in CD.

Figure 4

Efficacy of the serum leucine-rich alpha-2 glycoprotein (LRG) level as a biomarker for ulcerative colitis assessed using the Mayo endoscopic subscore (MES) (a) and for Crohn's disease assessed using the simple endoscopic score for Crohn's disease (SES-CD) (b). Receiver operating characteristic (ROC) curves for serum LRG and C-reactive protein (CRP) levels, as evaluated using the MES in ulcerative colitis (c) and the SES-CD in Crohn's disease (d). Values of the area under the ROC curve (AUC) are shown. Endoscopic remission was defined as MES ≤ 1 in UC and SES‐CD ≤ 4 in CD.

Figure 5

Leucine-rich alpha-2 glycoprotein (LRG) mRNA levels in peripheral blood mononuclear cells obtained from patients with ulcerative colitis, patients with Crohn's disease, and healthy control participants. The bars indicate the median ± 25^th percentile. The lower bar indicates the 10^th percentile, and the upper bar indicates the 90^th percentile.

Figure 6

Effect of antitumor necrosis factor- (TNF-) α agents on serum leucine-rich alpha-2 glycoprotein (LRG) levels in the patients with ulcerative colitis and those with Crohn's disease. For each disease, patients were divided into two treatment-based subgroups: patients taking anti-TNF-α agents and patients receiving any other medication. The bars indicate the median ± 25^th percentile. The lower bar indicates the 10^th percentile, and the upper bar indicates the 90^th percentile.