Leucine-rich Alpha-2 Glycoprotein Research Articles

LRG1 promotes atherosclerosis by inducing macrophage M1-like polarization

Atherosclerosis is a chronic inflammatory disease of the arterial wall characterized by the accumulation of cholesterol-rich lipoproteins in macrophages. How macrophages commit to proinflammatory polarization under atherosclerosis conditions is not clear. Report here that the level of a circulating protein, leucine-rich alpha-2 glycoprotein 1 (LRG1), is elevated in the atherosclerotic tissue and serum samples from patients with coronary artery disease (CAD). LRG1 stimulated macrophages to proinflammatory M1-like polarization through the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) pathways. The LRG1 knockout mice showed significantly delayed atherogenesis progression and reduced levels of macrophage-related proinflammatory cytokines in a high-fat diet-induced Apoe-/- mouse atherosclerosis model. An anti-LRG1 neutralizing antibody also effectively blocked LRG1-induced macrophage M1-like polarization in vitro and conferred therapeutic benefits to animals with ApoE deficiency-induced atherosclerosis. LRG1 may therefore serve as an additional biomarker for CAD and targeting LRG1 could offer a potential therapeutic strategy for CAD patients by mitigating the proinflammatory response of macrophages.

Leucine-rich alpha-2 glycoprotein is useful in predicting clinical relapse in patients with Crohn's disease during biological remission.

Serum leucine-rich alpha-2 glycoprotein (LRG) is a potential biomarker of Crohn's disease (CD). This study aimed to evaluate the usefulness of LRG in predicting clinical relapse in patients in remission with CD. This retrospective observational study assessed the relationships among patient-reported outcome (PRO2), LRG, and other blood markers. The influence of LRG on clinical relapse was assessed in patients in remission with CD. Data of 94 patients tested for LRG between January 2021 and May 2023 were collected. LRG level did not correlate with PRO2 score (ρ = 0.06); however, it strongly correlated with C-reactive protein (CRP) level (r=0.79) and serum albumin level (r=-0.70). Among 69 patients in clinical remission, relapse occurred in 22 patients (31.9%). In the context of predicting relapse, LRG showed the highest area under the curve, followed by CRP level, platelet count, and albumin level. Multivariate analysis revealed that only LRG (P= 0.02) was an independent factor for predicting clinical remission. The cumulative non-relapse rate was significantly higher in patients with LRG < 13.8 μg/mL than in patients in remission with LRG ≥ 13.8 μg/mL and normal CRP level (P= 0.002) or normal albumin level (P= 0.001). Cumulative non-relapse rate was also higher in patients with LRG < 13.8 μg/mL compared to those with LRG ≥ 13.8 μg/mL in patients with L3 or B2+B3 of Montreal calcification. LRG is useful in predicting clinical relapse in patients with CD during biological remission. LRG is a useful biomarker for predicting prognosis, even in patients with intestinal stenosis, or previous/present fistulas.

Leucine-rich alpha-2 glycoprotein is useful in predicting clinical relapse in patients with Crohn's disease during biological remission.

Serum leucine-rich alpha-2 glycoprotein (LRG) is a potential biomarker of Crohn's disease (CD). This study aimed to evaluate the usefulness of LRG in predicting clinical relapse in patients in remission with CD. This retrospective observational study assessed the relationships among patient-reported outcome (PRO2), LRG, and other blood markers. The influence of LRG on clinical relapse was assessed in patients in remission with CD. Data of 94 patients tested for LRG between January 2021 and May 2023 were collected. LRG level did not correlate with PRO2 score (ρ = 0.06); however, it strongly correlated with C-reactive protein (CRP) level (r=0.79) and serum albumin level (r=-0.70). Among 69 patients in clinical remission, relapse occurred in 22 patients (31.9%). In the context of predicting relapse, LRG showed the highest area under the curve, followed by CRP level, platelet count, and albumin level. Multivariate analysis revealed that only LRG (P= 0.02) was an independent factor for predicting clinical remission. The cumulative non-relapse rate was significantly higher in patients with LRG < 13.8 μg/mL than in patients in remission with LRG ≥ 13.8 μg/mL and normal CRP level (P= 0.002) or normal albumin level (P= 0.001). Cumulative non-relapse rate was also higher in patients with LRG < 13.8 μg/mL compared to those with LRG ≥ 13.8 μg/mL in patients with L3 or B2+B3 of Montreal calcification. LRG is useful in predicting clinical relapse in patients with CD during biological remission. LRG is a useful biomarker for predicting prognosis, even in patients with intestinal stenosis, or previous/present fistulas.

71821 - Comparisons of serum and urine concentrations of leucine-rich alpha-2 glycoprotein 1 (LRG1) in children with and without appendicitis

71821 - Comparisons of serum and urine concentrations of leucine-rich alpha-2 glycoprotein 1 (LRG1) in children with and without appendicitis

Efficacy of serum leucine-rich alpha-2 glycoprotein in predicting findings of Crohn's disease small bowel lesion in capsule endoscopy.

Small bowel capsule endoscopy (SBCE) is an evaluation method for small bowel (SB) lesions in Crohn's disease (CD). However, the relationship between SBCE findings and the serological biomarker leucine-rich alpha-2 glycoprotein (LRG) remains unclear. We aimed to establish appropriate cutoff values of LRG to predict the presence of SB lesions in CD through SBCE. Patients with CD with SB lesions who had undergone SBCE and LRG measurements 1 month before and after the SBCE were included. The LRG values for ulcers ≥0.5 cm and other inflammatory lesions noted in SBCE were determined using the Youden Index, and the sensitivity and specificity were calculated. Additionally, the correlation between the SBCE scores (CD Activity in Capsule Endoscopy) and LRG values was evaluated. Forty patients without active colorectal lesions were included in the study. When the cutoff value of LRG for SB ulcers ≥ 0.5 cm was set at 14 μg/mL, the sensitivity was 92.3%, specificity was 81.5%, positive predictive value (PPV) was 70.6%, and negative predictive value (NPV) was 95.7%. In contrast, an LRG cutoff value of 12 μg/mL without inflammatory findings had a sensitivity of 91.7%, specificity of 82.1%, PPV of 68.8%, and NPV of 95.8%. CD Activity in Capsule Endoscopy correlated well with LRG values (Spearman's rank correlation coefficient ρ = 0.681, P< 0.001). An LRG cutoff value of 14 μg/mL may be useful in predicting the presence of SB ulcers ≥ 0.5 cm, and an LRG cutoff value of 12 μg/mL may be useful in predicting the absence of SB inflammatory findings.

LEUCINE-RICH ALPHA 2 GLYCOPROTEIN: A USEFUL BIOMARKER TO DISCRIMINATE SMALL INTESTINAL MUCOSAL HEALING IN C-REACTIVE PROTEIN-NEGATIVE CROHN’S DISEASE

Abstract BACKGROUND The treatment goals for inflammatory bowel disease, including Crohn's disease (CD), have shifted from clinical remission to mucosal healing. However, frequent endoscopies burden patients. Leucine-rich alpha 2 glycoprotein (LRG), produced by hepatocytes, neutrophils, and the intestinal epithelium, is more gut-specific than C-reactive protein (CRP). We examined whether LRG, as a biomarker, can detect small intestinal mucosal healing in CD patients, especially in those who are CRP-negative. METHOD 1) This study examined CD patients who visited our department from May 2021 to April 2023, had LRG measured, and underwent image evaluation using capsule endoscopy or balloon-assisted endoscopy. We analyzed their clinical background, looked for a correlation between LRG and CRP, assessed the ROC-AUC of LRG and CRP for mucosal healing, and measured the LRG and CRP cutoff values to determine mucosal healing. 2) Next, in CRP-negative CD patients, we analyzed the ROC-AUC of LRG for mucosal healing and LRG cutoff value to determine mucosal healing. Endoscopic evaluation was done within 3 months before and after LRG measurement. Absent open ulcers indicated mucosal healing. The upper limit of normal CRP value was &amp;lt;3 mg/L. We used the Spearman correlation coefficient to determine the correlation. RESULTS 1) Here, 67 CD patients were analyzed; 43 (64%) were men. The median age (range) of onset was 25.6 (3-57) years. The median disease duration (range) was 7.6 (0-27) years. B1, B2, and B3 of Montreal Classification were established in 31 (46.2%), 21 (31.3%), and 15 (22.3%) patients, respectively. The median (range) of LRG was 21.7 (7.6-67.4) μg/mL. The median (range) of CRP was 10.8 (0.0-86.9) mg/L. LRG and CRP were strongly correlated (r=0.878, p&amp;lt;0.001). The ROC-AUC of LRG for mucosal healing was 0.839 (95% confidence interval [CI] 0.760-0.918). LRG cutoff value for discriminating mucosal healing was 15.5 μg/mL (sensitivity 77%, specificity 75%). The ROC-AUC of CRP for mucosal healing was 0.811 (95% CI 0.721-0.900). The CRP cutoff value to differentiate mucosal healing was 0.9 mg/L (sensitivity 55%, specificity 90%). 2) Forty CRP-negative CD patients were analyzed; 23 (57%) were men. The median age (range) of onset was 21.9 (3-57) years. The median disease duration (range) was 7.0 (0-27) years. B1, B2, and B3 of Montreal Classification were established in 17 (42.5%), 12 (30.0%), and 11 (27.5%) patients, respectively. The median (range) of LRG was 12.3 (7.6-23.5) μg/mL. The ROC-AUC of LRG for mucosal healing was 0.817 (95% CI 0.696-0.938). The LRG cutoff value to differentiate mucosal healing was 14.1 μg/mL (sensitivity 61%, specificity 76%). CONCLUSION LRG may be a better biomarker than CRP for assessing endoscopic remission of the small intestinal mucosa in CD. In CRP-negative CD patients, LRG level of ≥14.1 μg/mL could indicate small intestinal ulcers.

USEFULLNESS OF SERUM LEUCINE-RICH ALPHA2-GLYCOPROTEIN AND FECAL CALPROTECTIN ASSURROGATE MARKERS IN ULCERATIVE COLITIS

Abstract BACKGROUND AND AIM Serum Leucine-rich alpha-2 glycoprotein (LRG) was identified as a novel biomarker for rheumatoid arthritis and IBD by using a proteomics approach. Several studies have suggested that serum LRG levels and fecal calprotectin (fCal) were correlated with clinical activities in patients with ulcerative colitis (UC). We compared utility of these biomarkers for monitoring disease activity in UC. METHODS A single-center observational study was conducted at Kyushu University Hospital. A total of 101 patients who underwent colonoscopy during the period from February to December 2021 were enrolled. The associations between endoscopic and histological activity and biomarkers were investigated. Endoscopic activity was defined as Mayo endoscopic score (MES) of 1 or less for mucosal healing and 0 for complete mucosal healing. For histological activity (n=90), Geboes score of 2 or less was defined as histological remission. RESULTS Subjects ranged in age from 16 to 80 years (35 males and 66 females). There were 63 cases of total colitistype, 32 cases of left-sided colitis type, and 6 cases of proctitis type. The MES at enrollment were as follows: MES 0 in 41 cases, MES 1 in 33 cases, MES 2 in 19 cases, and MES 3 in 8 cases. In comparison between the mucosal healing and non-mucosal healing groups, LRG was significantly lower in the mucosal healing group (p&amp;lt;0.0001). The correlation coefficient of LRG with MES was r=0.614 (p&amp;lt;0.0001), which was higher than that of fCal, r=0.414 (p&amp;lt;0.0001). In ROC analysis with mucosal healing as the outcome, the AUC and cut-off value of LRG were 0.781 and 17.9 μg/ml, respectively, and for fCal were 0.850 and 396 μg/g, respectively. In the ROC analysis with complete mucosal healing as the outcome, the AUC for LRG was 0.690, which was lower than the AUC of 0.846 for fCal . When compared by histological remission, LRG was lower in the histological remission group (p&amp;lt;0.001). In the ROC analysis with histological remission as the outcome, the AUC for LRG was 0.722 (cutoff value 14.2 μg/ml) and for fCal was 0.837 (cutoff value 119 μg/g). CONCLUSION Both LRG and fCal are valuable biomarkers reflecting disease activity in UC.

P660 Serum Leucine-rich Alpha-2 Glycoprotein Can be a Biomarker for Selecting Anti-Cytokine Biologics in Patients with Inflammatory Bowel Disease: A Multicentre Prospective Cohort Study

Abstract Background Serum leucine-rich alpha-2 glycoprotein (LRG) is a biomarker reflecting endoscopic activity in patients with inflammatory bowel disease (IBD). However, it remains unclear whether serum LRG can predict the effectiveness of anti-cytokine biologics (biologics) in patients with IBD. This study aimed to evaluate whether serum LRG could predict the effectiveness and serum trough concentrations of biologics in patients with IBD. Methods This was a multicentre prospective cohort study including patients with IBD (including ulcerative colitis [UC] or Crohn’s disease [CD]) who received the biologics [ustekinumab (UST), anti-tumor necrosis factor (anti-TNF)] from January 2019 to March 2023 at 15 hospitals participating in the Osaka Gut Forum. The effectiveness of biologics was evaluated by clinical remission (CR) at week 8. We defined CR as a partial Mayo score of 2 or lower, with each subscore of 0 or 1 for UC and a CD activity index of &amp;lt; 150 for CD. Factors associated with CR at week 8 such as backgrounds, disease activities and concomitant medications at week 0 were analyzed by Cox proportional hazards model. For each biologic, we compared the effectiveness of biologics in the high LRG group with that in the low LRG group divided by the median serum LRG levels at week 0 (cut-off = 18.2 μg/mL). Results A total of 184 patients with IBD (UC, 80; CD, 104) were enrolled (UST/ anti-TNF, 119/ 65; biologic exposure, 31.5%; median disease duration, 6 years [Interquartile range (IQR) 1-14]). Median serum LRG levels at week 0 and serum C-reactive protein levels at week 0 were 18.2 μg/mL [IQR 12.5-28.1] and 0.19 mg/dL [IQR 0.03-0.77], respectively. At week 0, 63 (34.2%) and 64 (34.8%) patients concomitantly received corticosteroids and immunomodulators, respectively. In 184 patients with IBD, multivariate analysis revealed that serum LRG level at week 0 &amp;lt; 18.2 μg/mL was extracted as a significant factor for CR at week 8 (Odds ratio: OR 2.70, 95% confidence interval: CI 1.22-5.96). In patients who received UST, the proportion of CR at week 8 in the low-LRG group (76.9%) was significantly higher than that in the high-LRG group (59.3%, P = 0.038). In patients who received anti-TNF, however, the proportion of CR in the low-LRG group (84.6%) was not differ from that in the high-LRG group (82.1%, P = 0.781). Median serum trough concentrations of UST at week 8 in the low-LRG group (10.9 μg/mL, IQR 6.7-13.4) was significantly higher than that in the high-LRG group (5.3 μg/mL, IQR 2.4-8.3, P &amp;lt; 0.001). Conclusion Serum LRG could predict the effectiveness and serum trough concentrations of UST and be a biomarker for selecting biologics in patients with IBD.

Significance of Serum Leucine-rich Alpha-2 Glycoprotein as a Diagnostic Marker in Pediatric Inflammatory Bowel Disease.

Serum leucine-rich alpha-2 glycoprotein (LRG) has been utilized for adult inflammatory bowel disease (IBD); however, its efficacy in pediatric IBD remains unknown. The aim of this study was to compare the diagnostic accuracy of serum LRG for pediatric IBD with that of current inflammatory markers, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). This retrospective case-control study included pediatric patients, aged <16 years, who underwent colonoscopy and/or esophagogastroduodenoscopy between April 2017 and March 2022. All eligible patients were divided into two groups: patients with IBD, diagnosed with ulcerative colitis and Crohn's disease, and non-IBD controls. The optimal cut-off value of serum LRG for IBD diagnosis was determined from receiver operating characteristic analysis, and diagnostic accuracy of serum LRG was compared to serum ESR and CRP. A total of 53 patients (24 with IBD and 29 non-IBD controls) met the inclusion criteria. The cut-off value of serum LRG for IBD diagnosis was determined to be 19.5 μg/ml. At this cut-off value, serum LRG had a positive predictive value (PPV) of 0.80 and negative predictive value (NPV) of 0.88. In contrast, PPV and NPV were 0.78 and 0.70 for serum ESR and 0.82 and 0.72 for serum CRP, respectively. Serum LRG can be a potential diagnostic marker for pediatric IBD, with higher diagnostic accuracy than that of the conventional serum markers ESR and CRP.

The evaluation of salivary leucine-rich alpha-2 glycoprotein (LRG) and C-reactive protein (CRP) in humans with periodontal health or periodontal disease.

The purpose of the present research is to evaluate the salivary levels of leucine-rich alpha-2 glycoprotein (LRG) and C-reactive protein (CRP) in periodontal health and disease (gingivitis and stage III periodontitis) and also to compare the discriminative efficiencies of both biomarkers in periodontal disease. LRG is a new acute-phase protein whose functions are still being investigated. LRG and CRP are both biomarkers that are increased by inflammation. No clinical study has yet investigated the comparison of the level of LRG and CRP in periodontal health, gingivitis and periodontitis in saliva samples. A total of 60 individuals, including 20 periodontally healthy (control group/group C), 20 with gingivitis (group G), and 20 with Stage III periodontitis (group P), who were systemically healthy and non-smokers, participated in this study. Periodontal charts were used for recording clinical periodontal parameters and saliva LRG and CRP levels were measured by ELISA. Analyzing the area under the curve (AUC) was performed by the receiver-operating characteristics curve. Salivary levels of LRG and CRP were significantly higher in disease groups than in group C (p < .05). Positive statistically significant correlations were observed between both biomarkers and clinical parameters (p < .05). There was also a strong positive correlation between two biomarkers (p < .05). In distinguishing periodontal disease from periodontal health, LRG (AUC = 0.833) and CRP (AUC = 0.826) were found to have similar accuracy (p = .923). LRG and CRP may be useful and similarly effective biomarkers in the diagnosis of periodontal diseases based on the findings of this study.

Single-cell RNA sequencing unveils Lrg1's role in cerebral ischemia‒reperfusion injury by modulating various cells

Background and purposeCerebral ischemia‒reperfusion injury causes significant harm to human health and is a major contributor to stroke-related deaths worldwide. Current treatments are limited, and new, more effective prevention and treatment strategies that target multiple cell components are urgently needed. Leucine-rich alpha-2 glycoprotein 1 (Lrg1) appears to be associated with the progression of cerebral ischemia‒reperfusion injury, but the exact mechanism of it is unknown.MethodsWild-type (WT) and Lrg1 knockout (Lrg1−/−) mice were used to investigate the role of Lrg1 after cerebral ischemia‒reperfusion injury. The effects of Lrg1 knockout on brain infarct volume, blood‒brain barrier permeability, and neurological score (based on 2,3,5-triphenyl tetrazolium chloride, evans blue dye, hematoxylin, and eosin staining) were assessed. Single-cell RNA sequencing (scRNA-seq), immunofluorescence, and microvascular albumin leakage tests were utilized to investigate alterations in various cell components in brain tissue after Lrg1 knockout.ResultsLrg1 expression was increased in various cell types of brain tissue after cerebral ischemia‒reperfusion injury. Lrg1 knockout reduced cerebral edema and infarct size and improved neurological function after cerebral ischemia‒reperfusion injury. Single-cell RNA sequencing analysis of WT and Lrg1−/− mouse brain tissues after cerebral ischemia‒reperfusion injury revealed that Lrg1 knockout enhances blood‒brain barrier (BBB) by upregulating claudin 11, integrin β5, protocadherin 9, and annexin A2. Lrg1 knockout also promoted an anti-inflammatory and tissue-repairing phenotype in microglia and macrophages while reducing neuron and oligodendrocyte cell death.ConclusionsOur results has shown that Lrg1 mediates numerous pathological processes involved in cerebral ischemia‒reperfusion injury by altering the functional states of various cell types, thereby rendering it a promising therapeutic target for cerebral ischemia‒reperfusion injury.

Leucine-Rich Alpha-2 Glycoprotein 1 Accumulates in Complicated Atherosclerosis and Promotes Calcification.

Atherosclerosis is the primary cause of cardiovascular disease. The development of plaque complications, such as calcification and neo-angiogenesis, strongly impacts plaque stability and is a good predictor of mortality in patients with atherosclerosis. Despite well-known risk factors of plaque complications, such as diabetes mellitus and chronic kidney disease, the mechanisms involved are not fully understood. We and others have identified that the concentration of circulating leucine-rich α-2 glycoprotein 1 (LRG1) was increased in diabetic and chronic kidney disease patients. Using apolipoprotein E knockout mice (ApoE-/-) (fed with Western diet) that developed advanced atherosclerosis and using human carotid endarterectomy, we showed that LRG1 accumulated into an atherosclerotic plaque, preferentially in calcified areas. We then investigated the possible origin of LRG1 and its functions on vascular cells and found that LRG1 expression was specifically enhanced in endothelial cells via inflammatory mediators and not in vascular smooth muscle cells (VSMC). Moreover, we identified that LRG1 was able to induce calcification and SMAD1/5-signaling pathways in VSMC. In conclusion, our results identified for the first time that LRG1 is a direct contributor to vascular calcification and suggest a role of this molecule in the development of plaque complications in patients with atherosclerosis.

The Effect of High-intensity Functional Training on LRG1 Levels and Its Relationship with Cardiovascular Risk Factors and Atherogenic Indices in Overweight and Obese Women

Introduction: The present study aimed to investigate the effect of high-intensity functional training on leucine-rich alpha-2 glycoprotein 1(LRG1) levels and its relationship with cardiovascular risk factors and atherogenic indicators in overweight and obese women. Method: In this semi-experimental study, 19 overweight and obese women were randomly divided into two groups of high-intensity functional training (n=9) and control (n=10). The participants of the training group performed high-intensity functional exercises three times per week for eight weeks. Before and after the intervention, blood samples were taken to measure LRG1 concentration and lipid profile, in addition to the calculation of atherogenic indices. Analysis of covariance test was used to analyze the data. Results: After eight weeks of high-intensity functional training, LRG1 concentration (P=0.027), plasma atherogenic index (P=0.000), Castelli risk index-I (CRI-I) (P=0.001), and Castelli risk index-II (CRI-II) (P=0.002) were significantly decreased in the experimental group compared to the control group. A positive and significant correlation was observed between changes in LRG1 concentration and changes in body fat percentage (r=0.437, P=0.041), plasma atherogenic index (r=0.512, P=0.025), and CRI-I (r=0.479, P=0.038). A negative and significant correlation was observed between the changes of LRG1 and high-density lipoprotein cholesterol (HDL-C) (r =-0.569, P=0.011). Conclusion: Eight weeks of high-intensity functional training in overweight and obese women is effective in reducing LRG1 and improving cardiovascular risk factors and atherogenic indicators. Therefore, high-intensity functional exercises can be effective as auxiliary exercise interventions in controlling and reducing complications related to overweight and obesity

Biomarkers for Monitoring of Changes in Disease Activity in Ulcerative Colitis.

In recent years, various biomarkers of ulcerative colitis (UC) have emerged; however, few studies have simultaneously examined the utility of multiple biomarkers for monitoring disease activity. Additionally, serum leucine-rich alpha-2 glycoprotein (LRG), a new biomarker, may show a blunt response to anti-TNF antibody therapy. This prospective study explored effective biomarkers that could monitor disease activity changes in patients with UC. In addition, we examined the effect of anti-TNF antibody therapy on changes in LRG. Blood and stool samples were collected twice from patients with UC: at baseline and at least 8 weeks later. Changes in serum LRG, interleukin (IL)-6, prealbumin (pre-Alb), high-sensitivity C-reactive protein (hs-CRP), CRP, and fecal calprotectin (FC) were measured and correlated with changes in disease activity. The relationship between anti-TNF antibody therapy and LRG levels was also examined in patients with the same disease activity. Forty-eight patients with UC (96 samples) were analyzed. ΔLRG and ΔIL-6 correlated strongly with the change in the partial Mayo (pMayo) score between the two time points (ΔpMayo) (r = 0.686, 0.635, respectively). In contrast, FC and IL-6 were particularly accurate predictors of clinical remission, and their area under the curves (AUCs) were significantly higher than that of CRP (AUC: 0.81, 0.76 vs. 0.50; p = 0.001, 0.005). No association was found between the administration of anti-TNF antibody preparations and the LRG values. Correlations were found between changes in UC disease activity and LRG, IL-6, pre-Alb, hs-CRP, CRP, and FC. LRG reflects disease activity during anti-TNF antibody therapy.

Combination of leucine-rich alpha-2 glycoprotein and fecal markers detect Crohn's disease activity confirmed by balloon-assisted enteroscopy.

Endoscopic activity confirmed by enteroscopy is associated with poor clinical outcome in Crohn's disease (CD). We investigated which of the existing biomarkers best reflects endoscopic activity in CD patients including the small bowel, and whether their combined use can improve accuracy. One hundred and four consecutive patients with ileal and ileocolonic type CD who underwent balloon-assisted enteroscopy (BAE) from October 2021 to August 2022 were enrolled, with clinical and laboratory data prospectively collected and analyzed. Hemoglobin, platelet count, C-reactive protein, leucine-rich alpha-2 glycoprotein (LRG), fecal calprotectin, and fecal hemoglobin all showed significant difference in those with ulcers found on BAE. LRG and fecal calprotectin showed the highest areas under the curve (0.841 and 0.853) for detecting ulcers. LRG showed a sensitivity of 78% and specificity of 80% at a cutoff value of 13 μg/mL, whereas fecal calprotectin showed a sensitivity of 91% and specificity of 67% at a cutoff value of 151 μg/g. Dual positivity for LRG and fecal calprotectin, as well as LRG and fecal hemoglobin, both predicted ulcers with an improved specificity of 92% and 100%. A positive LRG or fecal calprotectin/hemoglobin showed an improved sensitivity of 96% and 91%. Positivity for LRG and either of the fecal biomarkers was associated with increased risk of hospitalization, surgery, and relapse. The biomarkers LRG, fecal calprotectin, and fecal hemoglobin can serve as noninvasive and accurate tools for assessing activity in CD patients confirmed by BAE, especially when used in combination.

Monitoring of leucine-rich alpha-2-glycoprotein and assessment by small bowel capsule endoscopy are prognostic for Crohn's disease patients.

Endoscopy is important to determine the effectiveness of treatment for Crohn's disease (CD), but searching the entire small intestine is difficult. Thus, we investigated the usefulness of leucine-rich alpha-2 glycoprotein (LRG), a new biomarker for predicting mucosal activity, in evaluating the activity of CD small intestinal lesions. This will further determine whether the results of small bowel capsule endoscopy (SBCE) affect the prognosis of patients with CD. A total of 114 patients with CD who underwent SBCE were included. We analyzed the correlation between LRG and Capsule Endoscopy Crohn's Disease Activity Index (CECDAI). The cutoff value of LRG to achieve mucosal healing was calculated using the receiver operating characteristic curve. Then, we compared the presence or absence of intervention and the relapse rate of patients who could not achieve mucosal healing. The CECDAI correlated with LRG. The calculated LRG value for achieving mucosal healing was ≤11.9. Ninety-one patients were in clinical remission at the time of SBCE. During the follow-up period, 17 patients relapsed. As a result of SBCE, when no treatment intervention was performed in the case of CECDAI ≥3.5, the relapse rate was significantly higher than when CECDAI <3.5 or intervention was performed in the case of CECDAI ≥3.5. The results reveal that LRG correlates with the activity of the entire small intestine and that SBCE assessment and therapeutic intervention can influence patient prognosis.

Combined serum albumin, fecal immunochemical test, and leucine-rich alpha-2 glycoprotein levels for predicting prognosis in remitting patients with ulcerative colitis

This study investigated the usefulness of serum leucine-rich alpha-2 glycoprotein (LRG) and fecal immunochemical tests (FIT) for predicting relapse in patients with ulcerative colitis (UC). Data of 194 patients tested for LRG between January 2020 and June 2022 were retrospectively collected and clinical characteristics were recorded. LRG was strongly correlated with CRP levels and it had a moderately negative correlation with albumin levels, whereas FIT was not significantly correlated with either CRP or albumin levels. Furthermore, the median serum albumin and FIT were significantly different between patients with or without clinical relapse; while the LRG level was not associated with clinical relapse. Although LRG is not an independent factor for predicting clinical relapse, the cumulative remission rate was significantly higher in patients with higher albumin than in those with lower albumin. Furthermore, the combination of FIT and albumin was useful for predicting for relapse, patients with higher FIT and lower albumin tended to have higher relapse rates than those with both lower FIT and albumin and those with lower FIT and higher albumin. Our study indicated that serum albumin level is useful for predicting relapse, even in remitting outpatients. Although LRG is not an independent factor for predicting clinical relapse, it is useful for identifying patients that are likely to relapse when combined serum albumin or FIT results.

The LRG-TGF-β-Alk-1/TGFßRII-Smads as Predictive Biomarkers of Chronic Hydrocephalus after Aneurysmal Subarachnoid Hemorrhage.

Chronic hydrocephalus is a common complication of aneurysmal subarachnoid hemorrhage (aSAH); however, the risk factors and the mechanisms underlying its occurrence have yet to be fully elucidated. The purpose of this study was to identify biomarkers that could be used to predict chronic hydrocephalus after aSAH and to investigate the relationships. We analyzed cerebrospinal fluid (CSF) samples from 19 patients with chronic hydrocephalus after aSAH and 44 controls without hydrocephalus after aSAH. Enzyme-linked immunosorbent assay was used to determine the levels of leucine-rich alpha-2-glycoprotein (LRG), transforming growth factor-β (TGF-β), Smad1, Smad4, Smad5, Smad8, activin receptor-like kinase 1 (Alk-1), activin receptor-like kinase 5 (Alk-5), P38, and TGF-β type II receptor (TGFßRII) in CSF samples. In the CSF of patients with chronic hydrocephalus after aSAH, the levels of LRG, TGF-β, Alk-1, Smad5, and TGFßRII were significantly increased (p < 0.05) and the levels of Smad1, Smad4, and Smad8 were significantly decreased (p < 0.05). There were no significant differences between the two groups concerning the levels of P38 and Alk-5 (p > 0.05). The analysis also identified significant correlations between specific biomarkers: LRG and Smad1, LRG and Smad5, TGF-β and Alk-1, and Alk-1 and Smad4 (p < 0.05); the Pearson's correlation coefficients for these relationships were -0.341, 0.257, 0.256, and -0.424, respectively. The levels of LRG, TGF-β, Alk-1, TGFßRII, Smad1/5/8, and Smad4 in the CSF are potentially helpful as predictive biomarkers of chronic hydrocephalus after aSAH. Moreover, the LRG-TGF-β-Alk-1/TGFßRII-Smad1/5/8-Smad4 signaling pathway is highly likely to be involved in the pathogenic process of chronic hydrocephalus after aSAH.

Serum leucine-rich alpha-2 glycoprotein levels for predicting active ultrasonographic findings in intestinal lesions of patients with Crohn's disease in clinical remission.

This study aimed to investigate the cutoff value of leucine-rich alpha-2 glycoprotein (LRG) in predicting active intestinal ultrasonography (IUS) findings in patients with Crohn's disease (CD) in clinical remission. Data were retrospectively collected from patients with CD evaluated using LRG and undergoing IUS from September 2020 to August 2022. Patients with a Harvey-Bradshaw Index of ≤4 were included and those who underwent intestinal resection were excluded. Bowel wall thickness and stratification and blood flow signal using superb microvascular imaging (SMI) were used to assess ultrasonography findings. SMI signals were categorized into 4 grades following the Limberg score. Receiver operating characteristic curves were constructed and the area under the curve was calculated to determine the LRG cutoff values for predicting active IUS findings and were compared with those of C-reactive protein. This study included 213 patients. The LRG cutoff values to predict active bowel wall thickness, loss of bowel wall stratification, and SMI of ≥1, ≥2, and 3 were 14.6 μg/mL, 14.6 μg/mL, 14.6 μg/mL, 14.6 μg/mL, and 16.9 μg/mL, respectively, with significantly higher areas under the curve in SMI of ≥1 and 3 than in C-reactive protein. The best LRG cutoff value for predicting active IUS findings was 14.6 μg/mL in patients with CD in clinical remission, suggesting that LRG is better than C-reactive protein for detecting active IUS findings in CD.

Serum leucine‐rich alpha‐2 glycoprotein in monitoring disease activity and intestinal mucosal healing for biotherapy‐naïve cases with ulcerative colitis

AbstractBackground and AimSerum leucine‐rich alpha‐2 glycoprotein level has been reported to be a useful biomarker in assessing mucosal healing in patients undergoing biotherapy, where mucosal lesions caused by ulcerative colitis are difficult to assess endoscopically. However, no such reports have been reported in biotherapy‐naïve cases.MethodsSixty‐eight patients with ulcerative colitis (UC) who were biotherapy‐naïve at Kindai University Hospital between October 2021 and October 2022 were enrolled. We prospectively examined the correlation between leucine‐rich alpha‐2 glycoprotein (LRG), C‐reactive protein (CRP), erythrocyte sedimentation rate (ESR), and Geboes scores with clinical endoscopic activity using the Mayo endoscopic subscore (MES).ResultsMucosal healing was achieved in 39 (57%) patients. Univariate analysis revealed that the factors associated with mucosal healing were LRG (P = 0.0024), CRP (P = 0.1078), ESR (P = 0.0372), and Geboes scores (P = 0.0075). Logistic regression analysis identified LRG and Geboes scores as independent factors associated with mucosal healing assessed using MES (P = 0.0431 for LRG and P = 0.0166 for Geboes scores).ConclusionLRG was found to be the easiest marker to monitor disease activity and mucosal inflammation in UC patients with biotherapy‐naïve cases, with a performance equivalent to that of Geboes scores.