Abstract
Background
Neutrophil gelatinase-associated lipocalin (NGAL) is a multi-potent 25-kDa protein mainly secreted by neutrophils. In inflammatory bowel disease (IBD), overexpression of NGAL in colon epithelium has been previously shown. This is the first study analyzing serum and urinary NGAL levels in IBD patients, with regard to specific characteristics of patients and disease.
Methods
Serum and urinary NGAL levels were determined in 181 patients with IBD, 93 with ulcerative colitis (UC), and 88 with Crohn’s disease (CD), 82 healthy controls (HC), and 41 patients with irritable bowel syndrome (IBS).
Results
Serum NGAL levels were elevated in IBD patients (88.19 ± 40.75 ng/mL) compared with either HC (60.06 ± 24.18 ng/mL) or IBS patients (60.80 ± 20.30 ng/mL), P < 0.0001. No significant difference was shown between UC (86.62 ± 35.40 ng/mL) and CD (89.92 ± 46.05 ng/mL). Significantly higher levels of serum NGAL were observed in patients with active (120.1 ± 38.46) versus inactive IBD (61.58 ± 15.98), P < 0.0001. Serum NGAL displayed a strong ability to distinguish active IBD from inactive disease, healthy controls, or IBS patients with a sensitivity of 100, 95, and 95% and a specificity of 68, 83, and 79%, respectively, performing better than erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) in the assessment of disease activity in both UC and CD. Urinary NGAL levels showed neither significant difference among patients and controls nor correlation with disease activity.
Conclusions
Serum NGAL is elevated particularly in active IBD and correlates with established markers of inflammation and disease activity, implicating its role in the pathophysiology of IBD.
Similar content being viewed by others
Abbreviations
- NGAL:
-
Neutrophil gelatinase-associated lipocalin
- IBD:
-
Inflammatory bowel disease
- UC:
-
Ulcerative colitis
- CD:
-
Crohn’s disease
- IBS:
-
Irritable bowel syndrome
- CRP:
-
C-reactive protein
- ESR:
-
Erythrocyte sedimentation rate
- eGFR:
-
Estimated glomerular filtration rate
References
Meijer MJ, Mieremet-Ooms MA, van der Zon AM, et al. Increased mucosal matrix metalloproteinase-1, -2, -3 and -9 activity in patients with inflammatory bowel disease and the relation with Crohn’s disease phenotype. Dig Liver Dis. 2007;39:733–9.
Nielsen BS, Borregaard N, Bundgaard JR, et al. Induction of NGAL synthesis in epithelial cells of human colorectal neoplasia and inflammatory bowel diseases. Gut. 1996;38:414–20.
Carlson M, Raab Y, Sevéus L, et al. Human neutrophil lipocalin is a unique marker of neutrophil inflammation in ulcerative colitis and proctitis. Gut. 2002;50:501–6.
Von Lampe B, Barthel B, Coupland SE, et al. Differential expression of matrix metalloproteinases and their tissue inhibitors in colon mucosa of patients with inflammatory bowel disease. Gut. 2000;47:63–73.
Nielsen OH, Gionchetti P, Ainsworth M, et al. Rectal dialysate and fecal concentrations of neutrophil gelatinase-associated lipocalin, interleukin-8, and tumor necrosis factor-alpha in ulcerative colitis. Am J Gastroenterol. 1999;94:2923–8.
Manfredi MA, Zurakowski D, Rufo PA, et al. Increased incidence of urinary matrix metalloproteinases as predictors of disease in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis. 2008;14:1091–6.
Devarajan P. Review: neutrophil gelatinase-associated lipocalin: a troponin-like biomarker for human acute kidney injury. Nephrology (Carlton). 2010;15:419–28.
Cowland JB, Sørensen OE, Sehested M, et al. Neutrophil gelatinase-associated lipocalin is up-regulated in human epithelial cells by IL-1 beta, but not by TNF-alpha. J Immunol. 2003;171:6630–9.
Bu DX, Hemdahl AL, Gabrielsen A, et al. Induction of neutrophil gelatinase-associated lipocalin in vascular injury via activation of nuclear factor-kappaB. Am J Pathol. 2006;169:2245–53.
Mishra J, Ma Q, Prada A, et al. Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. J Am Soc Nephrol. 2003;14:2534–43.
Malyszko J, Malyszko JS, Bachorzewska-Gajewska H, et al. Neutrophil gelatinase-associated lipocalin is a new and sensitive marker of kidney function in chronic kidney disease patients and renal allograft recipients. Transpl Proc. 2009;41:158–61.
Flo TH, Smith KD, Sato S, et al. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature. 2004;432:917–21.
Schmidt-Ott KM, Mori K, Li JY, et al. Dual action of neutrophil gelatinase-associated lipocalin. J Am Soc Nephrol. 2007;18:407–13.
Yan L, Borregaard N, Kjeldsen L, et al. The high molecular weight urinary matrix metalloproteinase (MMP) activity is a complex of gelatinase B/MMP-9 and neutrophil gelatinase-associated lipocalin (NGAL). Modulation of MMP-9 activity by NGAL. J Biol Chem. 2001;276:37258–65.
Gupta K, Shukla M, Cowland JB, et al. Neutrophil gelatinase-associated lipocalin is expressed in osteoarthritis and forms a complex with matrix metalloproteinase 9. Arthritis Rheum. 2007;56:3326–35.
Chakraborty S, Kaur S, Muddana V, et al. Elevated serum neutrophil gelatinase-associated lipocalin is an early predictor of severity and outcome in acute pancreatitis. Am J Gastroenterol. 2010;105:2050–9.
Eagan TM, Damås JK, Ueland T, et al. Neutrophil gelatinase-associated lipocalin: a biomarker in COPD. Chest. 2010;138:888–95.
Oikonomou K, Kapsoritakis A, Eleftheriadis T, et al. Renal manifestations and complications of inflammatory bowel disease. Inflamm Bowel Dis. 2011;17:1034–45.
Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders. Gastroenterology. 2006;130:1480–91. Erratum in: Gastroenterology. 2006;131:688.
Walmsley RS, Ayres RC, Pounder RE, et al. A simple clinical colitis activity index. Gut. 1998;43:29–32.
Lennard-Jones JE. Classification of inflammatory bowel disease. Scand J Gastroenterol Suppl. 1989;170:2–6; discussion 16–9.
Rachmilewitz D. Coated mesalazine (5-aminosalicylic acid) versus sulphasalazine in the treatment of active ulcerative colitis: a randomised trial. BMJ. 1989;298:82–6.
Best WR, Becktel JM, Singleton JW, et al. Development of a Crohn’s disease activity index. National Cooperative Crohn’s Disease Study. Gastroenterology. 1976;70:439–44.
Herget-Rosenthal S, Bökenkamp A, Hofmann W. How to estimate GFR-serum creatinine, serum cystatin C or equations? Clin Biochem. 2007;40:153–61.
Bolignano D, Della Torre A, Lacquaniti A, et al. Neutrophil gelatinase-associated lipocalin levels in patients with crohn disease undergoing treatment with infliximab. J Investig Med. 2010;58:569–71.
Mowat C, Cole A, Windsor A, et al. Guidelines for the management of inflammatory bowel disease in adults. Gut. 2011;60:571–607.
Li C, Chan YR. Lipocalin 2 regulation and its complex role in inflammation and cancer. Cytokine. 2011;56:435–41.
Himmel ME, Hardenberg G, Piccirillo CA, et al. The role of T-regulatory cells and toll-like receptors in the pathogenesis of human inflammatory bowel disease. Immunology. 2008;125:145–53.
Cario E. Toll-like receptors in inflammatory bowel diseases: a decade later. Inflamm Bowel Dis. 2010;16:1583–97.
Karlsen JR, Borregaard N, Cowland JB. Induction of neutrophil gelatinase-associated lipocalin expression by co-stimulation with interleukin-17 and tumor necrosis factor-alpha is controlled by IkappaB-zeta but neither by C/EBP-beta nor C/EBP-delta. J Biol Chem. 2010;285:14088–100.
Raices RM, Kannan Y, Bellamkonda-Athmaram V, et al. A novel role for IkappaBzeta in the regulation of IFNgamma production. PLoS One. 2009;4:e6776.
Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature. 2007;448:427–34.
Przybylowski P, Malyszko J, Malyszko J. Kidney function assessed by eGFR, cystatin C and NGAL (neutrophil gelatinase-associated lipocalin) in relation to age in heart allograft recipients. Med Sci Monit. 2010;16:CR440–4.
Gasche C, Lomer MC, Cavill I, et al. Iron, anaemia, and inflammatory bowel diseases. Gut. 2004;53:1190–7.
Keohane J, O’Mahony C, O’Mahony L, et al. Irritable bowel syndrome-type symptoms in patients with inflammatory bowel disease: a real association or reflection of occult inflammation? Am J Gastroenterol. 2010;105(1788):1789–94.
Schoepfer AM, Beglinger C, Straumann A, et al. Fecal calprotectin correlates more closely with the simple endoscopic score for Crohn’s disease (SES-CD) than CRP, blood leukocytes, and the CDAI. Am J Gastroenterol. 2010;105:162–9.
Vucelic B. Inflammatory bowel diseases: controversies in the use of diagnostic procedures. Dig Dis. 2009;27:269–77.
Acknowledgments
The authors would like to thank Dr. Dimitrios Nikoulis for his excellent technical assistance and Dr. George Krommydas for his contribution to statistical analyses conducted.
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Oikonomou, K.A., Kapsoritakis, A.N., Theodoridou, C. et al. Neutrophil gelatinase-associated lipocalin (NGAL) in inflammatory bowel disease: association with pathophysiology of inflammation, established markers, and disease activity. J Gastroenterol 47, 519–530 (2012). https://doi.org/10.1007/s00535-011-0516-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00535-011-0516-5