Inflammatory Bowel Diseases:
Clinical Review Articles
Clinical Utility of Fecal Biomarkers for the Diagnosis and Management of Inflammatory Bowel Disease
Kopylov, Uri MD*,†; Rosenfeld, Greg MD‡; Bressler, Brian MD‡; Seidman, Ernest MD*,†
*Division of Gastroenterology, McGill University Health Center, Montreal, Quebec, Canada;
†Department of Medicine, McGill University, Montreal, Quebec, Canada; and
‡Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Reprints: Ernest Seidman, MD, McGill Center for IBD, Montreal General Hospital C10.145, 1650 Cedar Ave, Montreal, QC H3G 1A4, Canada (e-mail: firstname.lastname@example.org).
The authors have no conflicts of interest to disclose.
E. Seidman: Research lab support, Abbvie and B. Bressler, Speakers Bureau Alpco.
Received December 01, 2013
Accepted December 19, 2013
Abstract: Diagnosis and monitoring of inflammatory bowel diseases rely on clinical, endoscopic, and radiologic parameters. Inflammatory biomarkers have been investigated as a surrogate marker for endoscopic diagnosis of inflammatory activity. Fecal inflammatory biomarkers such as calprotectin and lactoferrin are direct products of bowel inflammation and provide an accurate and noninvasive diagnostic and monitoring modality for Crohn's disease and ulcerative colitis. This report contains an overview of the currently existing literature pertaining to clinical implications of fecal biomarkers for diagnosis, monitoring, and prediction of outcomes of inflammatory bowel disease.
To optimize outcomes in patients with inflammatory bowel diseases (IBD), frequent monitoring is aimed at evaluating treatment efficacy, severity of disease, and risk for potential complications. Direct assessment of mucosal inflammation (“mucosal healing”) is the current gold standard measure of efficacy employed in clinical trials. However, frequent endoscopic assessment of mucosal healing is invasive, time-consuming, costly, and associated with certain risks and patient discomfort. Hence, a reliable surrogate marker capable of mirroring mucosal inflammatory activity is a much sought after clinical tool.
Clinical indices of activity are frequently used for this purpose, but their accuracy is compromised by substantial subjectivity, heavy reliance on symptoms, and equivocal correlation with endoscopic indices.1 Biochemical indices such as C-reactive protein (CRP) are important in daily clinical practice, but their sensitivity is limited, particularly in ulcerative colitis (UC), with at least 50% of active patients with UC having normal CRP levels.2 The specificity of an elevated CRP also limits the usefulness of this biomarker, particulary in patients with infections, rheumatoid, or other autoimmune disorders.3
As inflamed bowel mucosa contains an abundance of neutrophils, fecal neutrophil-derived inflammation markers such as fecal calprotectin (FC) and lactoferrin (LF) may provide a more accurate assessment of the inflammatory burden in the gut. Since the first reports on the clinical applications of FC,4 multiple studies evaluating its role in IBD have been published. This report contains an overview of the currently existing literature pertaining to clinical implications of fecal biomarkers for diagnosis, monitoring, and prediction of outcomes in IBD.
BIOCHEMICAL PROPERTIES OF FECAL BIOMARKERS
Several different markers have been evaluated, but few are used in clinical practice. FC and LF, both derived from intestinal mucosa granulocytes, are the 2 most frequently studied.5 In IBD, activation of the innate and adaptive immune system leads to infiltration of the intestinal mucosa by neutrophils and macrophages. Cytosolic proteins secreted by activated macrophages can be easily detected in stool. Specifically, the S100 proteins are a family of calcium binding proteins with S100A8 and S100A9 forming complexes commonly referred to as calprotectin. Phagocytes expressing calprotectin have been found at sites of inflammation related to IBD6 and FC levels are proportional to the influx of neutrophils into the intestinal mucosa.7
Calprotectin is a calcium and zinc-binding protein with versatile functions. It constitutes 60% of neutrophil cytosolic protein.4 Functions include antibacterial and antifungal activity, inhibition of metalloproteinases, and induction of apoptosis.8 Calprotectin is resistant to bacterial degradation and is evenly distributed through the feces and remains stable in stool for up to 1 week at room temperature.4 Calprotectin can be reliably measured by enzyme-linked immunosorbent assay (ELISA) using less than 5 g of stool.4 Multiple studies have shown a strong correlation of FC concentrations with active inflammation in the gut. The normal cutoff for FC varies from 50 to 200 μg/g stool, depending on the assay used.9 Recently, reliable and accurate point of care test (POT) allowing office-based or home-based testing with a very rapid turnaround time were introduced (see below).
LF is a member of the iron-transferring protein family that has antibacterial and antifungal properties. It is stored in neutrophil granules but also found in many other cells including intestinal epithelial cells. It is released from cells undergoing apoptosis.6 LF is resistant to proteolysis but has a lower stability than FC at room temperature.10 Multiple previous studies have shown LF to correlate with active inflammation endoscopically and based on clinical symptoms.10–16 The cutoff level most commonly used is 7.25 μg/g in adults and 29 μg/g in children ages 2 to 9 years. A rapid POT for fecal LF is also available.5,17
Another member of the S100 family of proteins, the macrophage cytosolic protein S100A12, like calprotectin, contributes to leukocyte recruitment into inflamed mucosa. S100A12 has also recently been studied as a biomarker in adult and pediatric patients with UC. S100A12 is evenly distributed throughout feces and stable at room temperature for 7 days.18 Levels of S100A12 allowed discrimination of IBD from irritable bowel syndrome (IBS) and healthy controls (HC) with sensitivities of 81% to 90% and specificity of 100%.19 Sidler et al20 have shown a similar high sensitivity and specificity for diagnosing active inflammation in children (97% for both) using a cutoff of 10 μg/g. Despite its stability and evidence of its high sensitivity and specificity, S100A12 has not been used widely in clinical practice, likely because it has not been shown to be superior to the more widely accessible calprotectin test.
M2-PK is a heterodimer of pyruvate kinase, an enzyme of the glycolytic pathway, which is expressed in rapidly dividing cells. Originally used as a marker of cell turnover in colorectal cancer, fecal M2-PK has been studied as a potential biomarker of active IBD because of the rapid cell turnover and division seen in IBD.21 Levels of M2-PK have been shown to be elevated in IBD and colorectal cancer, with a strong linear correlation, yielding a sensitivity and specificity of 73% and 74%, respectively.21 Furthermore, M2-PK was able to accurately differentiate active inflammation amongst patients with IBD versus those with inactive disease.21 In children, M2-PK has also been shown to be useful in distinguishing IBD from nonorganic disease.22 However, the commercial feasibility of M2-PK assays are hampered by the relatively short stability (2 d) of the protein.18
Matrix metalloproteinases (MMP) are also released from the neutrophils of the intestinal mucosa in patients with active IBD. MMP-9 was shown to be elevated in colonic biopsies from patients with active UC, and thus it has been examined as a fecal biomarker.23 A recent study by Annahazi et al24 showed that MMP-9 could be used to distinguish UC from IBS-D and HC. Using a cutoff of 0.245 ng/mL, MMP-9 was found to be 85.1% sensitive and 99.9% specific for active UC. Another study demonstrated similar results in the pediatric population where with a cutoff of 6.0 ng/mL. The sensitivity and specificity were 70.6% and 88.9%, respectively.23 A significant difference in levels between UC and CD was found, likely because of small bowel involvement. Further study is needed to determine the usefulness of this enzyme as a biomarker for active IBD.
Other Potential Biomarkers
Inflammatory cytokines and chemokines such as Il1, Il6, Il8, and TNFα, while potentially attractive as biomarkers because of their role in initiating and maintaining inflammation, are quite unstable and therefore, have a limited role as fecal biomarkers.6 Other neutrophil, mast cell, and eosinophil-related inflammatory mediators such as polymorphonuclear elastase,12 myeloperoxidase, and eosinophilic protein X25,26 have been studied as potential biomarkers with some success. However, they are not widely available, have short half-lives and lack evidence of clinical utility. The clinical experience with the less studied fecal biomarkers12,16,19–24,27–30 (excluding FC and LF) for diagnosis and monitoring of IBD is summarized in Table 1.
TABLE 1-a Clinical U...Image Tools
CLINICAL IMPLICATIONS OF FECAL BIOMARKERS FOR THE DIAGNOSIS AND MONITORING OF IBD
TABLE 1-b Clinical U...Image Tools
TABLE 1-c Clinical U...Image Tools
This section focuses on the use of FC and LF in IBD, because these biomarkers are much more commonly employed in clinical practice and the evidence-based data pertaining to their diagnostic accuracy are much more extensive.
Discriminating Between IBD and Functional Bowel Disorders
Symptoms of IBD frequently mimic or overlap those of irritable bowel disease. Utilization of a reliable noninvasive marker can both significantly reduce the need for endoscopy and increase the diagnostic accuracy in patients with small bowel CD beyond the reach of the colonoscope. Multiple studies have been devoted to evaluate the diagnostic accuracy of FC in patients with suspected IBD5,10,12,13,20,31–41 (Table 2) in pediatric and adult cohorts. A meta-analysis including 6 adult (670 patients) and 7 pediatric studies (371 patients) included only studies that prospectively evaluated patients suspected to have IBD and compared FC with endoscopy results.42 The pooled sensitivity and specificity of FC for discrimination between IBD and IBS was 0.93 (95% confidence interval [CI], 0.85–0.97) and 0.96 (CI, 0.79–0.99), respectively. In the pediatric studies, the sensitivity and specificity of FC was 0.92 (CI, 0.84–0.96) and 0.76 (CI, 0.62–0.86), respectively.42 Other studies comparing organic and “nonorganic” or functional gastrointestinal disease43 or colonic inflammation versus noninflamed colon39,41,44 gave similar results. The lower specificity in pediatric compared with adult studies (P = 0.048) is likely explained by the significantly lower proportion of control patients diagnosed with IBS in the pediatric cohort. The authors concluded that utilization of FC would reduce the required number of endoscopies for this indication 3-fold in adults and by 35% in children and adolescents. The sensitivity of LF for detecting bowel inflammation in this setting is similar, ranging between 86% and 92% with specificity 77% and 100%.10,12,13,45
TABLE 2-a Diagnostic...Image Tools
OTHER CAUSES OF ELEVATED FC
TABLE 2-b Diagnostic...Image Tools
FC was found to be elevated because of a number of non-IBD inflammatory etiologies.9,42,46–48 These include (Table 3) bacterial enteritis and colitis, eosinophilic esophagitis, microscopic colitis, peptic ulcer disease, colorectal cancer, polyps, diverticulitis, and NSAID-induced bowel damage resulting in degranulation of neutrophils.41,44,49–51 Levels of FC in patients with IBD were significantly higher than in those diagnosed with non-IBD inflammatory conditions, especially noninfectious causes. In untreated celiac disease, one study demonstrated significantly higher concentrations of FC compared with patients on a gluten-free diet and HC (117.2 μg/g [3.2–30.6] versus 3.7 μg/g [0.5–58.2], and 9.6 μg/g [1–70], respectively, P < 0.001).52 High FC levels in the IBD range have also been reported with gastric and colonic polyps and neoplasms.41,44 In a meta-analysis that included 30 prospective and retrospective studies evaluating the accuracy of FC for the diagnosis of IBD or colorectal cancer using histological diagnosis as the gold standard, the sensitivity and specificity for IBD were 95% and 91%, respectively. However, this fell to 36% and 71% for colorectal cancer, with FC levels being nonsignificantly higher in patients with colorectal cancer in comparison with HC.53 In studies including patients with IBS and HC, FC levels in IBS were similar or slightly higher than in HC but significantly lower than in patients with IBD.39,41,43,54
PREDICTION OF DISEASE LOCATION
The majority of studies did not demonstrate significant differences in FC levels between UC and CD, in adult or pediatric cohorts.35,55,56 In CD, FC is a reliable predictor of active inflammation in patients with both small bowel and colonic disease;23,57–59 however, the data pertaining to endoscopic and radiologic correlation are less extensive for small bowel disease. FC was accurate in prediction of abnormal small bowel radiology in CD with a 100% sensitivity and 91% specificity of the cutoff value of 61 μg/g for prediction of abnormal findings.60 A correlation of FC with a degree of intestinal wall inflammation as demonstrated by magnetic resonance enterography (MRE) was reported in a small series of hospitalized CD patients.61 In a study including 40 newly diagnosed patients with CD with complete ileocolonoscopy, the average levels of FC in colonic and small bowel CD were similar (890 and 830 μg/g, P = 1.0).62 However, in another study, a correlation of FC with endoscopic score (simple endoscopic score for Crohn's disease) or histologic degree of inflammation was higher in colonic versus ileal disease (simple endoscopic score for Crohn's disease, 0.317 versus 0.42 and histologic score, 0.311 versus 0.563 for small bowel and colon, respectively), with very similar results obtained for LF.14
CORRELATION WITH SMALL BOWEL VIDEOENDOSCOPY IN SMALL BOWEL CD
In patients with a clinical suspicion of CD but negative bidirectional endoscopy, videocapsule endoscopy (VCE) has proven to be an accurate, safe, and noninvasive diagnostic modality for evaluation of possible small bowel inflammation.63 In view of the high costs of this procedure and the risk of capsule retention (up to 1.5% in patients with suspected CD),64 a noninvasive screening tool may further improve both the safety and the cost-effectiveness of VCE for obscure CD. A recent study examined the role of FC in 70 patients suspected of CD with negative ileocolonoscopy and gastroduodenoscopy.65 Overall, 50% of the patients were found to have small bowel CD by VCE.65 All affected patients had a FC >100 μg/g. The diagnostic yield of FC >200 μg/g was 65%. Another study examined the diagnostic accuracy of FC and S100A12, another neutrophil-derived biomarker measurable in stool. The sensitivity, specificity, positive, and negative predictive values of FC (cutoff, 50 μg/g) and S100A12 (cutoff, 0.06 mg/g) for prediction of inflammatory small bowel lesions on VCE were 59%, 66%, 38%, and 82% and 59%, 71%, 42%, and 83%, respectively.28 Further studies are needed to establish the diagnostic benefit and the optimal cutoffs for the utilization of fecal biomarkers as a screening tool before referral for VCE.
REPRODUCIBILITY OF FC RESULTS
FC values can vary from day to day in patients with IBD. Several factors such as the amount of water in the stool and laboratory technique may influence the results, along with actual variations in secretion of FC. In a study that included 63 patients with CD, FC samples were obtained on 2 consecutive days and evaluated by ELISA. The kappa value for agreement between the levels was 0.335 (fair agreement) (SD 0.115; P < 0.0002). However, only 5% of the patients had a value that changed from positive to negative or vice versa (200 being the cutoff for a negative result).66 In a pediatric study, a day-to-day variation of less than 10% was demonstrated.34 These findings suggest that although this variation is rarely significant for clinical purposes, some prudence is advisable in interpretation of single test results. Repeated testing may be useful. In our experience, limiting evaluations to the first morning sample reduces intertest variability.
POT FOR MEASUREMENT OF FC AND LF
The gold standard method for determination of FC has been the ELISA. Although accurate, this method is somewhat cumbersome and relatively expensive, unless a full plate can be completed (40 samples in duplicate or 80 in simplicate). Since 2008, several rapid POT were introduced, allowing simple and rapid semiquantitative determination of FC levels in an office setting with a turnaround time of minutes as compared with hours for the ELISA method. Large head-to-head comparison studies with the traditional ELISA technique are lacking, albeit these rapid tests were evaluated in smaller studies with excellent results. Otten et al compared a POTkit (Prevista GmbH & Co KG, Munich, Germany) with a standard ELISA technique in a variety of gastrointestinal conditions. In endoscopy-proven IBD, the results for both techniques were similar, with area under the curve of 0.955 and 0.896 for ELISA and the rapid test, respectively. In an additional study that included 23 patients without IBD and 91 patients with IBD, ELISA (with a cutoff of <50 μg/g) was compared with a rapid kit (Prevent IDCalDetect; Preventis, Bensheim, Germany) with a manufacturer-provided cutoff of 15 μg/mg for positivity. The sensitivity and specificity reported for discrimination of IBD from IBS were 95.7% and 86.8% versus 100% and 94.5%, respectively, with Cohen's kappa value 0.69 for correlation.5 The correlation of rapid POT for LF was similar to that of FC (kappa value of 0.68 versus 0.67). The rapid test was also successfully evaluated for in-home use by the patients for monitoring disease activity in UC. The patients used the kit (CALPRO Inc, Oslo, Norway) independently and uploaded a digital photograph of the stool collection device's screen to a dedicated web server. The results were correlated with a conventional ELISA with a cutoff of 50 μg/g. The rapid test had an excellent correlation (r = 0.95) with the ELISA. The coefficient of variation for the home test photograph was <10%, with a sensitivity of 96.2% and a specificity of 90.1%.67 An additional kit (Calprotectin; Quantum Blue, Buhlmann Laboratories, Switzerland) was evaluated in a pediatric CD population, with a Spearman rho correlation of 0.94.68 In an additional study with 142 adult samples, a significant correlation of 89.4% between results obtained with Quantum Blue and the ELISA was demonstrated.69 In this study, a cutoff of 30 μg/g with a “grey zone” of 30 to 110 resulted in a better correlation with ELISA than the manufacturer-suggested cutoff value of 50 μg/g. In our experience, the Quantum Blue assay with high readouts tends to lose completely normal values (below cutoff of 88 μg/g), which is very important in discriminating between IBS and IBD.
MONITORING DISEASE ACTIVITY IN IBD
Various clinical indices have been used to assess disease activity in IBD, both in clinical practice and in clinical trials. However, most of these scores are based on patient symptoms. In recent years, treatment success paradigm in IBD has shifted towards healing the mucosal inflammation, believed to be a more robust predictor of the future course of the disease. The clinical indices used such as the Crohn's disease activity index (CDAI) rely heavily on subjective parameters and are poorly correlated with mucosal inflammation.70 Recently, the reliability of the CDAI has been questioned as in one study patients with IBS actually achieved higher scores than patients with CD.71 The preferred, more accurate assessment of mucosal healing does require repeated endoscopies. In this setting, fecal biomarkers provide an attractive alternative to invasive techniques.
Several studies have attempted to correlate the diagnostic accuracy of fecal biomarkers with other inflammatory activity markers, such as serum CRP, clinical, and endoscopic indices of activity11,14,57,72–78 (Table 4). Generally, both FC and LF (evaluated in fewer studies) were strongly correlated with endoscopic activity indices. In 3 studies employing the Crohn's Disease Endoscopic Index of Severity (CDEIS),14,72,74 the median Pearson r correlation value was 0.49 (0.26–0.79) and for lactoferrin, it was 0.77.14 The correlation with the simple endoscopic score for Crohn's disease was similar for both FC (0.53, 0.35–0.7512)11,14,57,77 and LF (0.627).15 In UC, the correlation of FC with endoscopic Mayo score,12,72 Rachmilevitz index,36 and modified Baron score75 was 0.72 (0.49–0.83) for CRP and 0.51 for LF.12 In CD, the correlation with clinical indices (CDAI, Harvey–Bradshaw index) was much weaker (0.27, 0.14–0.55). This is not surprising, taking in account the fact that the clinical indices rely heavily on subjective symptoms, which could be comparably elevated in IBS.71 The sensitivity and specificity of CRP was lower that of FC for both endoscopic disease activity in UC and CD.12,14,15,57,72,73,75–77 However, high sensitivity CRP was similar to that of FC for correlation with simple endoscopic score for CD (0.46 versus 0.45).11
TABLE 4-a Correlatio...Image Tools
TABLE 4-b Correlatio...Image Tools
Very high levels of FC on admission were associated with an increased risk of colectomy in a study that included 90 patients hospitalized for acute severe UC,79 with an area under the curve of 0.65 (P < 0.05). Kaplan–Meier analyses showed that 87% of the patients with an initial FC level over 1900 μg/g underwent a colectomy over the course of the next 13 months.
CORRELATION WITH RESPONSE TO TREATMENT
Fecal biomarkers were also evaluated as a monitoring tool to assess response to treatment. A majority of these studies evaluated patients treated with TNF inhibitors. In a study from Finland,78 15 patients were evaluated with ileocolonoscopy, FC, and LF before and 3 months after start of anti-TNF treatment. Eighty percent of the patients responded to treatment. Median CDEIS fell from 13.0 to 4.8 (P < 0.002) and CDAI from 158 to 68 (P < 0.005). The decrease in CDEIS and CDAI was paralleled by a decrease in FC from 1173 to 130 μg/g (P = 0.001) and LF from 105 to 2.7 μg/g (P = 0.001).78 FC levels normalized in patients, who achieved clinical remission, but did not change significantly from baseline level in nonresponders. In another study, 644 patients with IBD treated with anti-TNF antibodies were evaluated for clinical response and remission using the Harvey–Bradshaw index score, endoscopy (CDEIS), CRP, and FC. Endoscopic activity demonstrated a stronger correlation with FC and CRP than with the clinical index. Neither the clinical index nor CRP was reliable at identifying endoscopic remission. However, FC (using a cutoff value of 94 μg/g) identified endoscopic remission with a sensitivity of 84% and specificity of 74%.57 Another European study correlated FC levels with endoscopic response to infliximab in a cohort of 53 patients with active UC. Endoscopic remission defined by a Mayo score of 0 to 1 was achieved in 58% of the patients and was paralleled by a decrease of FC levels to <50 μg/g in all patients achieving remission. Moreover, a sharp decrease of FC levels as early as week 2 from the initial infusion was well correlated with endoscopic remission at week 10. FC <50 μg/g or a decrease of 80% predicted remission with a specificity of 67% and sensitivity of 54%.80 This observation may have a significant clinical application allowing early evaluation of response to treatment and prompt identification of patients in need of dose intensification or additional treatment modifications. In a follow-up study, patients with UC were followed prospectively after achieving response to infliximab with serial endoscopic and clinical evaluations and FC measurements. A group of patients in sustained deep remission (defined as partial Mayo score <3 at all times with an endoscopic score of 0 to 1 at week 52) had FC levels below 40 μg/g at all time points. Patients who flared had significantly higher calprotectin levels (median >300 mg/kg) 3 months before the flare. Two consecutive calprotectin measurements of >300 mg/kg with an 1-month interval were identified as the best predictor of a flare (61.5% sensitivity and 100% specificity). FC level at the moment of relapse was significantly better correlated with endoscopic index than the blood CRP concentration (area under the curve, 0.85 versus 0.58; P <0.015).81
Little data exist on correlation of fecal biomarkers with endoscopic outcomes and mucosal healing in randomized prospective clinical trials in IBD. In a recent abstract evaluating this correlation in patients with active UC treated by Tofacitinib, an oral Janus Kinase Inhibitor, an FC cutoff of 150 μg/g achieved the highest summation of specificity and sensitivity for clinical remission (0.79 and 0.68, respectively; kappa, 0.44) and endoscopic remission (0.75 and 0.79, respectively; kappa, 0.38), considered fair to good correlation.82 Additional data from randomized prospective clinical trials may provide important high-quality data on the relative accuracy of the clinical and biological activity markers (including fecal biomarkers) for prediction of mucosal healing.
DISTINGUISHING IBS-RELATED SYMPTOMS IN IBD
Patients with IBD, especially those with CD, frequently present with nonspecific symptoms that may overlap with those of IBS. Identification of patients with symptoms that are not associated with mucosal inflammation is of considerable importance, because it may prevent unnecessary escalation of IBD treatment. Patients in clinical remission defined by clinical indices had 31% prevalence of IBS-related symptoms defined by Rome criteria.83 The levels of FC were much lower than those reported by other studies for active CD, yet higher than those associated with IBS without IBD.32,37 Interestingly, FC levels were not significantly different in patients with CD with and without IBS symptoms (111 μg/g versus 45.5 μg/g, respectively, P = 0.17). In another study, the levels of FC were similar in patients with CD and clinical remission with and without IBS-related symptoms (42 ± 11.6 (21–65) and 38.3 ± 9.8 (20–67), P = 0.3), with very similar results observed for UC.84 An important limitation of these studies is the lack of endoscopic ascertainment of remission, as FC assays were compared with clinical, but not endoscopic, indices. Although data are limited, the current literature suggests that in patients with clinical remission and IBS-related symptoms, the FC levels should be expected to be significantly lower than in active IBD. Studies employing endoscopic definitions of remission may provide more accurate data on the expected cutoff values of FC in this challenging patient cohort.
PREDICTION OF RELAPSE
Several studies evaluated calprotectin as a predictor of relapse in patients in clinical remission in both UC and CD43,85–89 (Table 5). In a recent meta-analysis of these studies, the pooled sensitivity and specificity of FC to predict relapse of quiescent IBD within 12 months was 78% (95% CI, 72–83) and 73% (95% CI, 68–77), respectively, with comparable accuracy in UC and CD. Within the cohort of patients with CD, FC seemed to be more accurate in prediction of relapse in ileocolonic and colonic disease. However, the data on isolated small bowel CD was limited.90 In UC, a recent study evaluated the cost-effectiveness of an inflammation-based treatment strategy for quiescent disease (that included adjustment of mesalamine dosage from 2.4 g/d to 4.8 g/d if active inflammation was detected by FC test performed once every 3 mo) with strategies based on treatment of symptomatic relapse only with or without baseline mesalamine treatment. FC-based strategy was the least costly strategy, while achieving similar clinical efficacy.91
FC and LF have been studied as potential biomarkers to detect early recurrence of disease postsurgical resection before onset of symptoms.92 FC and LF levels have been shown to normalize by 2 months postoperatively with any subsequent rise in levels correlating with recurrence of active gut inflammation.93 FC and LF levels were strongly correlated with each other and with endoscopic indices of disease activity.93 A recent study by Lobaton et al94 looked at FC levels in 29 patients with CD who had undergone ileocecal resection. FC levels were able to distinguish between those with no postoperative recurrence as demonstrated by a Rutgeert's scores of 0 to 1 and those with evidence of recurrence (2–4). FC levels were significantly different using both an ELISA and the rapid quantitative test. The ELISA provided a sensitivity of 75% and a specificity of 72% using a cutoff value of 203 μg/g, and the rapid test has a sensitivity of 67% and 72% with a higher cutoff of 283 μg/g.95 Another study found similar results whereby using a cutoff of 200 μg/g at 3 months postresection. The sensitivity of FC was 63% and the specificity was 75% for postoperative recurrence. This study also compared FC with ultrasound for the detection of postoperative recurrence and found FC more sensitive but less specific.92 Nevertheless, others have found high levels of LF and FC in postoperative patients who remain in clinical remission based on a rise in the CDAI.96 The interpretation of these results is questionable give that the correlation between clinical symptoms and endoscopic disease activity is poor. Further research with larger numbers of patients is necessary to confirm the utility of these promising biomarkers for the early detection of postoperative recurrence.
FC has been evaluated as an indicator of pouchitis in patients who have undergone proctocolectomy with ileoanal pouch anastomosis for UC. CRP as a biomarker in this setting has a low accuracy. FC has been shown to correlate with the frequency of pouchitis in the pediatric age group even after as long as 11 years postpouch creation.97 In this study, FC levels were correlated with no history, a single episode or recurrent episodes of pouchitis.97 For FC levels >300 μg/g, the sensitivity and specificity for recurrent pouchitis were 57% and 92%, respectively. A smaller study showed that a single morning FC sample was highly correlated with a 24-hour calprotectin level and was able to predict the presence of active inflammation due to pouchitis.98 Higher levels of FC have been reported in patients with pouch creation for severe UC compared with those with pouches for familial adenomatous polyposis, consistent with the known higher risk of pouchitis in patients with UC.99
LF has been shown to be able to distinguish irritable pouch syndrome from pouchitis, cuffitis, and CD with a sensitivity of 100% and a specificity of 85%, using a cutoff of 7 μg/g.100 LF has also been used to confirm the resolution of pouchitis post antibiotic therapy.101 In this study, LF was 100% sensitive and 92% specific for biopsy-proven pouchitis. For the 7 patients who were treated for pouchitis, LF was able to accurately predict the resolution or persistence of pouchitis.101
M2-PK levels have been shown to correlate with objective pouchitis scores, the pouch disease activity index and the endoscopic and histologic appearances of active inflammation, with a sensitivity of 80% and a specificity of 70.6%.27 Similar findings were obtained in another study where M2-PK levels were significantly higher in those with pouches than in HC.102 Furthermore, even higher levels were evident in those with a pouch disease activity index >7 suggesting active pouchitis. FC, LF, and M2-PK all may represent viable alternatives to pouchoscopy and biopsy for both diagnosis and evaluation of response to treatment.
Fecal biomarkers such as FC and LF provide accurate and convenient tools for screening of IBD in the setting of patients with symptoms consistent with either IBD or IBS. They are also useful for the management and monitoring of patients with IBD in various clinical situations. Fecal biomarkers reflect mucosal inflammation and are better correlated with mucosal healing than CRP or clinical indices. Rapid POT further improve the accessibility and the feasibility of fecal biomarkers, without compromising accuracy. Utilization of these markers can significantly reduce the number of invasive procedures needed for diagnosis and monitoring of IBD.
Several additional directions need to be explored to further optimize the utilization of fecal biomarkers in IBD. Primarily, it is important to understand whether fecal biomarkers can be true surrogates of mucosal healing, with the same impact on the natural history of IBD. Recently, complete mucosal healing (Mayo score of 0) with histologic healing have been suggested to be better associated with long-term prognosis than the commonly used definition of a Mayo score <2.103 It is currently unclear whether and how fecal biomarkers can serve as reliable surrogate markers for these novel treatment goals. When using FC for monitoring of disease activity and response to treatment, the optimal testing time after induction treatment needs to be established. It is also unclear whether measuring change from baseline levels will provide more accurate estimation of response than relying on absolute cutoff values that may vary significantly between individual patients.
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Crohn's disease; ulcerative colitis; fecal biomarkers; fecal calprotectin; lactoferrin; C-reactive protein
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