REVIEW ARTICLE Fecal Biomarkers in the Diagnosis and Monitoring of Crohn’s Disease Emily K. Wright, MD,* Peter De Cruz, MD, PhD,* Richard Gearry, MD, PhD, † Andrew S. Day, MD PhD, † and Michael A. Kamm, MD, PhD* Abstract: The diagnosis and monitoring of Crohn’s disease has traditionally relied on clinical assessment, serum markers of inflammation, and endoscopic examination. Fecal biomarkers such as calprotectin, lactoferrin, and S100A12 are predominantly derived from neutrophils, are easily detectable in the feces, and are emerging as valuable markers of intestinal inflammation. This review focuses on the role of fecal biomarkers in the diagnosis and monitoring of Crohn’s disease, in particular how these biomarkers change with disease activity and remission, how they can be used to monitor the response to medical therapy, their value in predicting clinical relapse, and their role in monitoring the postoperative state. (Inflamm Bowel Dis 2014;20:1668–1677) Key Words: Crohn’s disease, inflammatory bowel disease, stool tests, fecal biomarkers, calprotectin, lactoferrin, S100A12, postoperative D iagnosis and monitoring of Crohn’s disease activity is based on a combination of clinical assessment, serological markers of inflammation, and endoscopy. However, there is often insuffi- cient correlation between these tests to engender confidence in their routine use. 1–3 Endoscopy is widely accepted as the gold standard for detecting and quantifying bowel inflammation, but endoscopy is expensive, labor intensive, inconvenient for the patient, and carries some risk. Furthermore, standard ileocolono- scopy does not examine the small intestine proximal to the distal terminal ileum. The correlation between clinical scoring systems, such as the Crohn’s Disease Activity Index (CDAI) and the Har- vey–Bradshaw Index (HBI), and endoscopic findings in Crohn’s disease is poor. 4,5 The correlation between serum biochemical markers of inflammation, such as C-reactive protein (CRP), and endoscopic findings in Crohn’s disease is also inconsistent 5,6 with more than one-third of patients with clinically or endoscopically active disease having a normal CRP. 7,8 Simple, inexpensive, and safe tests that correlate closely with endoscopic findings are there- fore required to assist in the diagnosis and monitoring of disease. DEFINITIONS AND APPLICATIONS The most extensively described fecal biomarkers in the literature are fecal calprotectin (FC) and lactoferrin (FL). 9–15 These 2 biomarkers will form the basis of this review. S100A12, like FC, is a calgranulin and is emerging as a useful marker of gut inflammation. Literature on the use of S100A12 in inflammatory bowel disease (IBD) is limited and mainly con- tained to pediatric studies and will be explored briefly in this review. These biomarkers have the advantage of showing excel- lent stability in the feces at room temperature for up to 1 week before freezing until the time of analysis. 11,12,16,17 Table 1 sum- marizes the characteristics of these fecal biomarkers. Quantification is traditionally performed using the inexpensive and simple enzyme-linked immunosorbent assay (ELISA) technique with as little as 1–2 g of feces. Commercially available immunoassays have also become available recently, often referred to as “rapid tests”; these allow for fast and mobile point-of- care testing with as little as 40 mg of stool. 13–16,18 These rapid tests are simple and reliable alternatives to ELISA. They are useful in the clinical setting at a comparable cost and allow for the possibility of home testing as part of patient self-management. 18–22 Day-to-day variability of FC has been reported. 23,24 Moum et al 25 looked at FC variability in patients with Crohn’s disease. They found that although there was some variation, this was most significant when FC concentration exceeded 200 mg/L with only 5% of patients with a normal FC, defined as ,50 mg/L, having a paired test result of .50 mg/L. 25 Most recently, Naismith et al 26 confirmed these findings in patients with clinically quiescent Crohn’s disease. In this latter study, patients provided 3 stool sam- ples on 3 consecutive days with the overall consistency across 3 samples being high with an intraclass correlation of 0.84 (95% confidence interval [CI], 0.79–0.89) where a value of .0.80 re- flects almost perfect agreement, confirming low day-to-day vari- ability of FC in patients with Crohn’s disease. This supports the use of a single FC measurement in the clinical setting in the assessment of patients with Crohn’s disease. Received for publication April 7, 2014; Accepted April 21, 2014. From the *St. Vincent’s Hospital and University of Melbourne, Melbourne, Australia; and † Christchurch Hospital and University of Otago, Christchurch, New Zealand. The authors have no conflicts of interest to disclose. Reprints: Michael A. Kamm, MD, PhD, St. Vincent’s Hospital, Victoria Parade, Fitzroy, 3065 Melbourne, Australia (e-mail: mkamm@unimelb.edu.au). Copyright © 2014 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000087 Published online 10 June 2014. 1668 | www.ibdjournal.org Inflamm Bowel Dis  Volume 20, Number 9, September 2014 Downloaded from https://academic.oup.com/ibdjournal/article/20/9/1668/4579341 by guest on 12 August 2023