When There is Smoke, There May be Fire: Functional Abdominal Pain and the Role of Inflammation
Article Outline
Abbreviations: FAP, Functional abdominal pain, GI, Gastrointestinal, IBS, Irritable bowel syndrome, NSAID, Nonsteroidal antiinflammatory drugs
Recent advances in our understanding of the role of serotonin in the enteric nervous system and its relationship to intestinal visceral hyperalgesia have contributed significantly to the understanding of functional abdominal pain (FAP) and irritable bowel syndrome (IBS). Serotonin is an important gastrointestinal signaling molecule that activates intrinsic and extrinsic primary afferent neurons initiating peristaltic and secretory pathways, as well as mediating sensation leading to visceral hyperalgesia.1 This increased understanding has helped shift the paradigm that these disorders are exclusively behavioral in nature and that pathophysiological disturbances at the molecular level exist. Previous intestinal inflammation, bacterial overgrowth, and dysregulation of intestinal immunity have also been postulated to be important in the pathogenesis of visceral hypersensitivity.2 To date, the consideration of active ongoing inflammation and intestinal pain has been reserved for such conditions as Crohn's disease and ulcerative colitis where there is obvious bloody diarrhea, fever, and associated mucositis correlating with abnormal laboratory investigation.
See related article, p 646
In this issue of The Journal, Shulman et al3 continue to expand our knowledge on FAP and IBS by exploring the relationship of subclinical inflammation and its relationship to chronic pain of the gastrointestinal tract. They report the findings of a well-designed, prospective controlled study investigating the difference in gastrointestinal (GI) permeability and fecal calprotectin (marker for intestinal inflammation) concentration in children with FAP and IBS versus control subjects. The study consisted of 93 children with FAP/IBS recruited from both general and subspecialty pediatric practices and 52 “healthy” children recruited from the same pediatricians through a medical chart review.
Proximal GI permeability, as well as colonic permeability, was found to be significantly greater in the FAP/IBS group compared with the control group. Fecal calprotectin was also significantly higher in the FAP/IBS group. Fecal calprotectin concentration correlated with pain interference with activities. There was no correlation between GI permeability and pain-related symptoms, as well as no correlation between permeability and fecal calprotectin with stool form.
On meeting the eligibility requirements, a home visit was scheduled during which written consent and assent was obtained, and the Rome II Clinical Diagnostic Questionnaire for Pediatric Gastrointestinal Disorders was completed.4 Children and their parents were trained on how to collect urine and stool specimens and how to record pain and stooling episodes. Gastrointestinal permeability was measured via a 3-hour urine collection after an overnight fast and the consumption of a solution containing sucrose, lactulose, mannitol, and sucralose. Children also kept a 2-week diary recording pain intensity by use of a visual analogue scale and the degree to which pain interfered with activity by use of a previously described rating scale. Stooling patterns were tracked daily with a condensed Bristol stool chart.
Despite weekly visits from the research coordinators, there were significant per-protocol violations, including those who did not provide adequate stool specimens for calprotectin measurement and those who did not complete the 2-week diary. This amounted to almost 20% of the study population. No explanation is given for these violations. One possibility may be a difference between those participants who are research naïve and those who have participated in clinical research before.
Of the original 109 children with FAP/IBS and 66 control subjects who were recruited for this study, 10 children with FAP/IBS and 11 control children were excluded from the study as outliers because of abnormally high permeability ratios. It is concerning that these control children have such high permeability ratios; this warrants a more detailed discussion to justify this particular control population and the validity of the permeability tests.
Furthermore, not all of the children in the FAP/IBS group and control population underwent a standardized evaluation (such as endoscopy, celiac serologic study, etc) because they were recruited from a variety of clinical practice situations. The possibility of missing a diagnosis of known organic gastrointestinal illness such as celiac disease, Helicobacter pylori, inflammatory bowel disease, or carbohydrate malabsorption still exists. In addition, no distinction was made between children with FAP and IBS with predominant constipation and IBS with predominant diarrhea. Without this separation into subgroups, no comment can be made about whether the results are more or less applicable to one subgroup versus another. Those excluded from the study included those with organic gastrointestinal diseases, chronic conditions with possible intestinal manifestations (eg, cystic fibrosis), those with “alarm” features such as an abnormal physical examination result, and those receiving nonsteroidal antiinflammatory drugs (NSAIDs) or glucocorticoids. The association of NSAID use and high fecal calprotectin concentrations and the possibility of false-positive results, as well the effects of NSAIDS on intestinal permeability is somewhat unclear5, 6, 7, 8 but, in our opinion, deserves further discussion.
The use of chronic GI medications such as laxatives and gastrointestinal motility agents was only considered an exclusion criterion if there had been associated symptom relief. Recent data, however, have shown that these medications may lead to intestinal permeability changes. Alterations in the colonic flora and intestinal permeability with evidence of immune activation have been reported in chronic constipation, another functional gastrointestinal disorder.9 The aim of those investigators was to examine systemic immunity, the fecal flora, and intestinal permeability in patients with chronic constipation, under basal conditions and after therapy with the laxative bisacodyl. They assessed intestinal permeability, fecal flora analysis, T- and B-lymphocyte numbers, T-cell subpopulations, lymphocyte proliferation, phagocytosis, intracellular killing of Staphylococcus aureus by neutrophils, as well as circulating levels of immunoglobulins, immune complexes, and antibacterial antibodies in patients with functional constipation. In 12 patients with severely delayed transit, investigations were repeated after therapy with bisacodyl. Serum ovalbumin concentrations were higher in constipated patients (28.2 ± 4.1 ng/ml vs 1.0 ± 0.4 ng/mL, P < .05). Elevated counts of CD3+, CD4+, and CD25+ cells, increased spontaneous proliferation of lymphocytes, elevated titers of antibodies to Escherichia coli and S aureus, diminished counts of CD72+ B cells, diminished lymphocyte proliferation under phytohemagglutinin stimulation and a diminished phagocytic index for both neutrophils and monocytes were found in the constipated patients. Concentrations of Bifidobacterium and Lactobacillus were significantly lower in constipated patients; potentially pathogenic bacteria or fungi were increased. Therapy with bisacodyl resulted in normalization of the fecal flora, a reduction in ovalbumin concentration and return toward normal for certain immunologic variables. They concluded that constipation is associated with striking changes in the fecal flora, intestinal permeability, and the systemic immune response. Relief of constipation tends to normalize these findings, suggesting that these changes are caused by, rather than a cause of, constipation.
The protein calprotectin, found in neutrophils and monocytes, may be the more specific protein, if a true noninvasive biomarker is to be used in evaluating patients with persistent gastrointestinal complaints. In pediatric patients with undiagnosed gastrointestinal symptoms, elevated fecal calprotectin is an accurate maker of colorectal inflammation and thereby helpful in selecting patients who require colonoscopy to exclude inflammatory bowel disease.
A previous study was conducted to determine whether >50 μg of fecal calprotectin per gram was predictive of colorectal inflammation and did not have bacterial gastroenteritis, celiac disease, or any other chronic inflammatory disease.10
Study results showed that children with colonoscopy-proven colorectal inflammation have significantly higher levels of fecal calprotectin than did those without colorectal inflammation (median, 349 μg/g vs 16.5 μg/g; P < .001). Moreover, with an upper reference limit of 50 μg/g, calprotectin testing had a sensitivity of 95%, specificity of 93%, positive predictive value of 95%, and negative predictive value of 93%.
A separate study yielded somewhat less encouraging results, finding that fecal calprotectin can help distinguish organic causes of chronic diarrhea from IBS more effectively in children than in adults.11 Using a cutoff value of 50 μg of calprotectin per gram of stool, in adults the test had a sensitivity of 64% and a specificity of 80% in detecting organic causes of gastrointestinal symptoms. Among the adult patients with levels >50 μg/g, the assay had 70% positive and 74% negative predictive values for identifying organic causes of diarrhea. Among children, the test was more accurate in ruling out organic causes, with a sensitivity of 70%, specificity of 93%, and positive predictive value of 56%.
Despite these significant limitations and the missed opportunity to discuss the differences between the subsets of patients with IBS and FAP, Shulman et al3 should be congratulated. Their unique and original study with noninvasive techniques increases our understanding on subclinical inflammatory disease that exists in functional gastrointestinal disorders. The work here is increasingly important if we are to augment our understanding of the pathophysiology and design effective interventions for FAP and IBS, which affect up to 20% of school aged children. Until recently, FAP, IBS, and other functional gastrointestinal disorders were believed to be “psychosocial disorders with physical symptoms.” This study serves as further evidence that these disorders are in reality “physical disorders” with organic disease and with associated local inflammation that may yet be completely understood. So perhaps when there is smoke, there may be fire.
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PII: S0022-3476(08)00496-4
doi:10.1016/j.jpeds.2008.06.001
© 2008 Mosby, Inc. All rights reserved.
Refers to article:
- Increased Gastrointestinal Permeability and Gut Inflammation in Children with Functional Abdominal Pain and Irritable Bowel Syndrome , 09 June 2008
