Letter to the Editor: Leucine-rich α-2-glycoprotein in Taiwanese inflammatory bowel disease: Strengths and limitations of a novel serum marker

Abstract

Endoscopy and fecal calprotectin remain the reference standards for assessing inflammatory bowel disease activity, but their invasiveness and inconvenience have stimulated interest in serum biomarkers that better reflect mucosal inflammation. In their prospective study, Chen et al published a study in World Journal of Gastroenterology evaluated leucine-rich α-2-glycoprotein (LRP), a 50-kilodalton protein released from neutrophils, as a predictor of endoscopic activity in Taiwanese patients with ulcerative colitis and Crohn’s disease. LRP showed significant correlations with established markers and incremental diagnostic value when combined with C-reactive protein, hemoglobin, and albumin, particularly in ulcerative colitis with low C-reactive protein. Building on this data, this Letter discusses methodological and clinical considerations for interpreting LRP performance across inflammatory bowel disease phenotypes and burdens, including the impact of disease distribution, treatment exposure, and assay cutoffs on diagnostic accuracy. However, limitations of the study include its single-center cohort in Taiwan and the relatively modest performance of LRP compared with fecal calprotectin.

Key Words: Leucine-rich α2 glycoprotein; Inflammatory bowel disease; Ulcerative colitis; Crohn’s disease; Endoscopic activity; Serum biomarker; Fecal calprotectin

Core Tip: Leucine-rich α-2-glycoprotein (LRG) is an emerging serum biomarker that showed modest but incremental value for predicting endoscopic activity in Taiwanese patients with ulcerative colitis and Crohn’s disease, particularly when combined with C-reactive protein, hemoglobin, and albumin. This Letter highlights methodological issues and clinical implications of LRG testing, including its lower accuracy than fecal calprotectin, single-center data, and lack of standardized cutoffs, and argues that future multicenter, multi-ethnic studies should position LRG within composite biomarker panels and stepwise algorithms for noninvasive assessment of inflammatory bowel disease activity.

TO THE EDITOR

The prospective study published in World Journal of Gastroenterology by Chen et al[1] on leucine-rich α-2-glycoprotein (LRG) in Taiwanese patients with inflammatory bowel disease provides timely data on an emerging serum biomarker for endoscopic activity. The author has demonstrated LRG as a supportive marker, particularly when combined with C-reactive protein (CRP), hemoglobin, and albumin, but also underscored important limitations compared with fecal calprotectin (FC) and the need for validation beyond a single-center cohort. This Letter briefly highlights these strengths and weaknesses and outlines future research directions to clarify how LRG can be integrated into practical, patient-centered algorithms for noninvasive inflammatory bowel disease (IBD) monitoring.

STUDY EVALUATION

Chen et al[1] reports a prospective, single-center study assessing LRG as a serum biomarker of endoscopic activity in Taiwanese patients with IBD[1] (Figure 1). LRG is a 50-kilodalton glycoprotein released from activated neutrophils and other inflammatory cells and has been implicated as a potential biomarker in immune mediated diseases[2-6]. The investigators enrolled 203 patients [100 with ulcerative colitis (UC) and 103 with Crohn’s disease (CD)] and obtained serum, stool, and clinical data within one month of endoscopy, using the Mayo endoscopic subscore for UC and the Simple Endoscopic Score for CD as reference standards. LRG levels were compared with FC, CRP[7], hemoglobin, and albumin, and diagnostic performance was evaluated using correlation analyses and receiveroperating characteristic curves. This design directly addresses an important clinical gap: The need for blood-based markers that are more acceptable to patients than endoscopy or stool sampling, yet still reflect mucosal inflammation.

Figure 1 Prospective Taiwanese inflammatory bowel disease cohort and study workflow. The schematic diagram represents the single-center cohort of 203 patients (100 with ulcerative colitis, 103 with Crohn’s disease). Serum leucine-rich alpha-2 glycoprotein, C-reactive protein, hemoglobin, albumin, and fecal calprotectin were collected by the researchers within 1 month of endoscopy and analyzed against Mayo endoscopic subscore (ulcerative colitis) or Simple Endoscopic Score for Crohn’s disease as reference standards. UC: Ulcerative colitis; CD: Crohn’s disease; LGR: Leucine-rich alpha-2 glycoprotein; CRP: C-reactive protein; FC: Fecal calprotectin; MES: Mayo endoscopic subscore; SES-CD: Simple Endoscopic Score for Crohn’s disease.

The main strengths of the study lie in its rigorous methodology and clinically relevant endpoints. Active endoscopic disease is clearly defined, biospecimens are collected within 1 month of endoscopy, and LRG performance is examined separately in UC and CD. In general, all IBD patients showed a significant positive correlation of LRG[8] with FC (r = 0.155, P = 0.028) and CRP (r = 0.565, P = 0.001), which was more striking in UC patients, while in CD patients, LRG was strongly correlated with CRP. In contrast, LRG showed a negative correlation with hemoglobin and albumin. To evaluate diagnostic probability, accuracy, as well as optimal cutoff for each biomarker for predicting active disease, a receiver operating characteristic curve analysis was performed based on the results observed from the endoscopically active vs inactive group, which revealed significant differences in LRG, CRP, and FC levels. Quantitatively, in UC, the area under the curve (AUC) for predicting endoscopic activity is 0.54 for CRP, 0.56 for LRG, and 0.77 for FC, underscoring the superior standalone performance of FC and only modest discrimination by LRG alone. In CD, the corresponding AUCs are 0.69 for CRP, 0.60 for LRG, and 0.72 for FC, with no statistically significant differences between the three biomarkers. Most notably, among UC patients with low or normal CRP, combining CRP, hemoglobin, and LRG increases the AUC from 0.56 to 0.76, approaching the performance of FC (AUC = 0.78) while remaining slightly lower. These data support a nuanced conclusion that LRG adds the most incremental value in UC patients with low or normal CRP, where traditional serum markers underperform, and blood-based assessment is particularly challenging. In these settings, LRG appears best suited as part of a composite serum panel, rather than as a standalone test, with FC remaining the dominant noninvasive biomarker when stool testing is feasible (Figure 2). A concise way to summarize these findings is shown below (Table 1).

Figure 2 Summary of biomarker performance for predicting endoscopic activity in ulcerative colitis and Crohn’s disease. Comparative visualization of the area under the curve values for C-reactive protein (CRP), leucine-rich alpha-2 glycoprotein (LRG), and fecal calprotectin is shown. Additionally, it includes the composite model combining CRP, hemoglobin, and LRG in ulcerative colitis patients with low or normal CRP. It illustrates that LRG provides modest standalone discrimination but improves diagnostic accuracy when used in serum-based composite panels. UC: Ulcerative colitis; CD: Crohn’s disease; LGR: Leucine-rich alpha-2 glycoprotein; CRP: C-reactive protein; FC: Fecal calprotectin; AUC: Area under the curve; Hb: Hemoglobin.

Table 1 Diagnostic probability of leucine-rich alpha-2 glycoprotein, C-reactive protein, and fecal calprotectin to detect active endoscopic disease in ulcerative colitis and Crohn’s disease patients with low C-reactive protein levels.

Biomarker/model	Disease group	AUROC	Cutoff	Sensitivity	Specificity	Key point
CRP	UC	0.475 (0.321-0.629)	0.045	50%	60%	Weak discrimination compared with endoscopy
LRG	UC	0.654 (0.509-0.799)	7.15	77%	53%	Modest standalone performance
FC	UC	0.779(0.656-0.903)	35	77%	73%	Best single biomarker in UC
CRP + hemoglobin-LRG	UC, low/normal CRP	0.76 (0.52-0.82)	NA	88%	49%	Improves accuracy, close to FC (0.78)
CRP	CD	0.542 (0.298-0.785)	0.025	80%	36%	Moderate performance
LRG	CD	0.517 (0.232-0.801)	7.05	80%	50%	Lower than CRP and FC
FC	CD	0.639 (0.344-0.933)	37.5	80%	58%	The highest AUC among the three in CD

AUROC: Area under the receiver operating characteristic curve; UC: Ulcerative colitis; CD: Crohn’s disease; LGR: Leucine-rich alpha-2 glycoprotein; CRP: C-reactive protein; FC: Fecal calprotectin; AUC: Area under the curve.

Several limitations temper enthusiasm for immediate clinical implementation. First, FC consistently outperforms LRG for predicting endoscopic activity in both UC and CD, with higher AUCs that are in line with prior literature, reinforcing FC’s status as the dominant noninvasive biomarker. Second, the study is conducted at a single tertiary center in Taiwan, and the authors appropriately acknowledge that genetic background, environmental exposures, diet, and healthsystem factors may limit generalizability to other Asian and non-Asian populations. Third, although the paper discusses “optimal” LRG cutoffs, there remains substantial variability compared with prior predominantly Japanese cohorts, highlighting the lack of assay harmonization and the risk of overfitting thresholds to a single cohort. Taken together, these issues suggest that, at present, LRG should be viewed as a supportive adjunct to established markers, rather than a replacement for FC.

Overall, this work provides valuable human data extending LRG research beyond Japanese populations and clarifies where LRG is most likely to be clinically useful. Future research should prioritize multicenter, multiethnic validation with standardized LRG assays, direct head-to-head comparisons of different cutoff strategies, and evaluation of LRG within treat-to-target frameworks that incorporate clinical, endoscopic, and patient-reported outcomes. Such work will be essential to determine whether adding LRG meaningfully improves long-term disease control, healthcare utilization, and patient quality of life beyond existing biomarker-based strategies.

Moreover, as noted by the authors, biomarker data collection was done one month after endoscopy, which is essentially a long gap, which potentially could reduce the accuracy of the data due to the short half-life of these acute-phase biomarker proteins. Hence, further future validation of the data at closer time points to endoscopy would be important for comparing the diagnostic probability accuracy. Larger, multicenter, multi-ethnic studies using standardized assays and integration into treat-to-target algorithms will be required to determine whether incorporating LRG into routine practice meaningfully improves noninvasive monitoring and long-term outcomes in IBD. Longitudinal studies that assess LRG-based panels against treat-to-target endpoints and stratify performance by treatment exposure, disease extent, and phenotype would further clarify their clinical utility.

CONCLUSION

In conclusion, the study by Chen et al[1] provides important prospective evidence that serum LRG can serve as a supportive blood-based biomarker of endoscopic activity in Taiwanese patients with IBD, particularly in UC with normal or low CRP levels. Nonetheless, its diagnostic performance remains slower than that of FC, and the single-center design and variable cutoff values limit generalizability across populations and assay platforms. Current data therefore support using LRG as a complementary component within serum-based composite panels, or as an adjunct when FC is unavailable or impractical, rather than as a replacement for FC.