This prospective study in a large cohort of patients examined the use of calprotectin measurement in feces as a diagnostic test to identify clinically significant gastrointestinal findings in patients with abdominal discomfort referred for endoscopy. We provide the following new information: Patients with clinically significant findings at endoscopy had higher fecal calprotectin values than patients without; fecal calprotectin measured before endoscopy reliably predicted the presence of significant findings throughout the gastrointestinal tract; fecal calprotectin provided valuable diagnostic ability for significant findings in the upper intestinal tract but performed less well compared to findings in the colon; the diagnostic performance was independent of age > 50 years, an important risk factor for organic disease; and calprotectin levels indicated disease severity in patients with mucosal lesions of the stomach.
These findings are of clinical importance as they encourage the use of this simple and easily available biomarker in the diagnostic approach to patients with abdominal discomfort, especially to decide upon the necessity to perform endoscopy. Patients with fecal calprotectin levels > 50 μg/g should receive either esophagogastroduodenoscopy (EGD) or colonoscopy according to clinical presentation and if negative, follow-up endoscopy, as the prevalence of significant findings with negative initial endoscopy reached 57% in these patients.
Over the last decade, the number of endoscopies performed by gastroenterologists has steadily increased both in the USA and in Europe [28, 29]. Given the limited resources and ever increasing health-care costs, optimizing the appropriate selection of patients for endoscopy is crucial. Unfortunately, selection based on symptoms is not reliable; even when compared to an expert panel, individual gastroenterologists tend to overestimate the appropriateness of endoscopies they perform . The Danish Dyspepsia Group found clinical diagnosis of epigastric pain for more than two weeks unreliable and half of all patients with peptic ulcer or reflux esophagitis were misclassified . In another study, neither age nor the presence of alarm features were effective predictors of endoscopic findings in patients with upper abdominal pain . The diagnostic yield of colonoscopy in patients with symptoms other than bleeding or diarrhea was shown to be equal to a screening population  and average risk patients with non-specific abdominal symptoms have similar rates of adenomatous polyps as asymptomatic patients [33, 34]. Both the American Society for Gastroenterological Endoscopy (ASGE) and the European Panel on the Appropriateness of Gastrointestinal Endoscopy (EPAGE) have released guidelines in an attempt to optimize patients selection for endoscopy [35–37]. Applying these guidelines yielded significantly more findings for appropriate than for inappropriate endoscopies, but the selection criteria suffered from low specificity [38, 39].
Calprotectin is a calcium binding protein of neutrophil granulocytes that correlates well with neutrophil infiltration of the intestinal mucosa when measured in feces, has antimicrobial activity, and is resistant to enzymatic degradation both in vivo and in vitro [9, 40]. Accordingly, as a marker of neutrophilic intestinal inflammation, calprotectin values might reflect a composite endpoint for organic intestinal disease. In fact, a mean sensitivity and specificity of 83% and 84%, respectively, has been reported for calprotectin to distinguish organic from non-organic disorders in patients with abdominal discomfort . To separate IBD from non-IBD, the diagnostic accuracy is even higher. Mean sensitivity and specificity was 93% and 96%, respectively, in a recent meta-analysis . Altogether, those studies suggest that elevated fecal calprotectin levels reflect the presence of mucosal inflammation and thus may be used to detect organic disease of the gastrointestinal tract, especially in symptomatic patients.
The value of fecal calprotectin in consecutive patients referred for endoscopy has been poorly studied. In an Italian study, fecal calprotectin was measured in consecutive unselected outpatients undergoing colonoscopy and was found to be elevated in a majority of patients with colorectal cancer and inflammatory conditions of the colon but also in 36% patients with normal endoscopic findings . The negative predictive of fecal calprotectin was 96%.
Our study measured fecal calprotectin in 538 consecutive patients with abdominal discomfort referred for endoscopy. We found that fecal calprotectin was highly useful in the assessment of this important group of patients as it reliably distinguished patients with clinically significant gastrointestinal findings from patients without. Therefore, we confirm findings of prior studies [10–13], but expand the results obtained in these specific patient groups to an unselected group of consecutive patients with abdominal discomfort. It is a remarkable strength of this study that we did not investigate selected patients or patient groups with high clinical suspicion for a specific disorder. In our study, fecal calprotectin provided valuable diagnostic assistance in a heterogeneous patient population. Accordingly, our results favor measurement of fecal calprotectin prior to endoscopic investigation of patients with abdominal discomfort.
Our study further showed that fecal calprotectin had good diagnostic ability also in patients with significant findings of the upper intestinal tract. Previously, elevated fecal calprotectin values have been reported in peptic ulcer disease and gastric cancer [19, 20] but the diagnostic value in consecutive patients referred for EGD has never been systematically examined. We found calprotectin to be a valuable biomarker in the evaluation of upper abdominal discomfort; especially when considering the initial clinical approach to these patients is still open to debate. Currently, prompt endoscopy is usually recommended to evaluate new onset dyspepsia for patients over 45 years or with alarm features to rule out malignancy , but using these criteria, the high sensitivity to detect relevant findings or new malignancies (82% and 97%) was substantially impaired by low specificity (26% and 20%) . In our study, using fecal calprotectin gave a lower sensitivity (59%) but provided a much higher specificity (84%).
Fecal calprotectin values of patients with esophagitis LA grade A (mucosal breaks < 5 mm, limited to a single mucosal fold) were similar than in patients with normal findings (Table 2). This finding merits special consideration. In the LA system, grading of esophagitis has been limited to erosions in an attempt to increase inter-observer agreement. However, for esophagitis grade A, considerable inter-observer variability has been described (kappa value 0.167) . Endoscopic grading of esophageal erosions is far from perfect, especially for smaller lesions, and this might have contributed to the low sensitivity of fecal calprotectin to detect espohagitis grade A. The impaired sensitivity should be recognized and integrated in the clinical evaluation of patients with abdominal discomfort, especially in the presence of concomitant reflux symptoms.
The diagnostic precision was uniformly high, both in younger patients (age < 50 years) with a low pretest probability, and older patients at higher risk for organic intestinal disease. We also cannot confirm that fecal calprotectin values increase with age in patients with normal findings on endoscopy, as suggested from data in healthy volunteers .
All together, those results support the concept that fecal calprotectin is a useful marker in the evaluation of patients with abdominal discomfort and that a biomarker-guided strategy might have additional value to a strategy using clinical decision, including guidelines of appropriateness, to decide on endoscopy. It is important to recognize that these results apply only to symptomatic patients with abdominal discomfort. Especially screening endoscopies such as colonoscopy should be performed irrespective of calprotectin values. Fecal calprotectin has not been established as screening tool for colorectal cancer in asymptomatic patients.
Several limitations of the study merit consideration. First, our prospectively defined endpoint was the presence of a clinically significant finding. Indeed, classification of findings in clinical practice is challenging and endoscopic findings might not always be congruent with abdominal discomfort presented by the patient. Second, in several important gastrointestinal disorders, such as small bowel bacterial overgrowth, celiac disease, or food lactose intolerance, fecal calprotectin levels will be normal [45, 46]. Third, we did not systematically assess the presence of mucosal lesions in the small-bowel. We acknowledge, that this is a limitation of our study as increased fecal calprotectin has been shown in small-bowel enteropathy . In the 15 patients who had small bowel capsule endoscopy no significant lesion were found. Fourth, there have been reports of elevated calprotectin values in expectorations of patients with acute and chronic pulmonary disease . This might have influenced fecal measurement of calprotectin.