Unexplained Symptoms and Hidden Inflammation in Patients With Crohn’s Disease
Authors: Dario Sorrentino, Vu Q. Nguyen
Journal: Clinical Gastroenterology and Hepatology (2019)

We read with interest the article by Colombel et al1Colombel J.F. et al.Clin Gastroenterol Hepatol. 2019; 17: 380-390Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar on functional gastrointestinal symptoms in patients with inflammatory bowel disease (IBD). They propose invaluable guidance to manage an unsolved issue in patients with Crohn’s disease (CD) and ulcerative colitis, diseases for which the mechanisms of pain and diarrhea are still incompletely understood. We fully agree that a stepwise approach to rule out ongoing inflammation in IBD patients with persistent symptoms is of paramount importance. We also agree that consideration should be given to anatomic/mechanical abnormalities especially in patients undergone any type of abdominal surgery. Here we would like to focus on the accuracy of available tests to exclude small bowel inflammation as the cause of unexplained symptoms in CD patients. We have recently published a retrospective study2Sorrentino D. et al.Inflamm Bowel Dis. 2018; 24: 1566-1574Crossref PubMed Scopus (20) Google Scholar in which 43 consecutive CD patients underwent capsule endoscopy (CE) because of symptoms unexplained by colonoscopy and/or imaging including magnetic resonance enterography (MRE) and/or computed tomography enterography (CTE). Patients were also tested for fecal lactoferrin (FL) and C-reactive protein (CRP), inflammatory markers also recommended by Colombel et al1Colombel J.F. et al.Clin Gastroenterol Hepatol. 2019; 17: 380-390Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar in their diagnostic approach. We started to question the accuracy of standard tests in CD patients who continued to experience pain and diarrhea despite being apparently in full remission (as determined by negative colonoscopy, FL, and MRE/CTE); however, they reported immediate benefit by empirical courses of prednisone. These patients later underwent CE, which often showed widespread small bowel inflammation. Overall, in our patients, imaging was negative with a positive CE in up to 75% of cases. Furthermore, CRP and FL were within limits in up to 42% and 32% of cases, respectively, in patients with positive CE findings. Ileocolonoscopy, when positive, would have been insufficient for disease staging (ie, inflammation was above the reach of the colonoscope) in up to 60% of cases. Findings were even more surprising in postoperative CD patients because it is generally assumed that surgery completely removes the disease (on the basis of resection margins and preoperative staging by imaging). In such patients a negative colonoscopy is considered synonymous with surgically induced remission.3Benevento G. et al.Expert Rev Gastroenterol Hepatol. 2010; 4: 757-766Crossref PubMed Scopus (30) Google Scholar It has been known for some time that in CD, CE can detect small bowel lesions otherwise undetected by other imaging techniques and that lesions can be present in the small bowel proximally to the reach of the colonoscope especially in postoperative patients. The discrepancy between imaging and CE has been attributed to the low sensitivity of MRE and CTE for luminal inflammation not involving deeper intestinal wall layers.4González-Suárez B. et al.Inflamm Bowel Dis. 2018; 24: 775-780Crossref PubMed Scopus (37) Google Scholar, 5Kopylov U. et al.Dig Liver Dis. 2017; 49: 854-863Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar However, such CE findings have often been dismissed as clinically irrelevant. In our study we demonstrated that CE findings changed the patient management (ie, initiation or escalation of therapy) in up to 50% of cases. Importantly, in >80% of these cases the CE-driven management change led to clinical and biochemical improvement after up to 18 months of follow-up. Because the sensitivity of inflammatory markers in exclusive small bowel CD can be low,6Sipponen T. et al.Scand J Gastroenterol. 2012; 47: 778-784Crossref PubMed Scopus (72) Google Scholar normal values in the presence of lesions at CE are not unexpected.7Vijayan S. et al.UEG Journal. 2017; 5: A703Google Scholar, 8Aggarwal V. et al.Gastrointest Endosc. 2017; 86: 1070-1078Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Such inaccuracy might argue against their reliability in conclusively ruling out small bowel inflammation in CD patients (including those operated on) with negative imaging and colonoscopy. In conclusion, our and other studies show that in a considerable number of cases CE is the only diagnostic tool capable of ruling out small bowel inflammation, which could be at the basis of symptoms in CD patients thought to be in biologic remission because of normal ileocolonoscopy, imaging, and markers of inflammation. The use of CE appears especially important in symptomatic CD patients after surgery, a scenario in which symptoms are often attributed to surgery itself (short bowel, inflammation caused by surgery, altered anatomy, adhesions, bacterial overgrowth, or bile salt diarrhea). Undetected small bowel lesions should also be taken into account when staging the disease and estimating the total disease burden in individual patients. They can also significantly impact the results of clinical trials probing medications to treat or prevent postoperative relapse because the endpoints invariably include mucosal inflammation. Larger confirmatory and prospective studies are clearly needed in the future to examine the role of CE in CD diagnosis, staging, and monitoring, possibly using new devices that are capable of visualizing the small bowel and colon at once. In the meantime, Colombel et al1Colombel J.F. et al.Clin Gastroenterol Hepatol. 2019; 17: 380-390Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar should be commended for their effort to establish rationale guidelines to help clinicians manage this difficult issue. AGA Clinical Practice Update on Functional Gastrointestinal Symptoms in Patients With Inflammatory Bowel Disease: Expert ReviewClinical Gastroenterology and HepatologyVol. 17Issue 3PreviewDescription: The purpose of this clinical practice update review is to describe key principles in the diagnosis and management of functional gastrointestinal (GI) symptoms in patients with inflammatory bowel disease (IBD).Methods: The evidence and best practices summarized in this manuscript are based on relevant scientific publications, systematic reviews, and expert opinion where applicable.Best practice advice 1: A stepwise approach to rule-out ongoing inflammatory activity should be followed in IBD patients with persistent GI symptoms (measurement of fecal calprotectin, endoscopy with biopsy, cross-sectional imaging). Full-Text PDF