PRESENTATION

Irritable Bowel Syndrome and Other Functional Gastrointestinal Disorders

Ilkay Simsek, MD

Abstract: Irritable bowel syndrome is one of several highly prevalent functional gastrointestinal disorders (FGID) displaying symptoms of gastrointestinal dysmotility and visceral hypersensitivity. Substantial overlap of symptoms and comorbidities occur not only between irritable bowel syndrome and other FGID but also with gastrointestinal disorders that are not related to motility (eg, celiac disease and lactose intolerance) and to somatic conditions (eg, bromyalgia and chronic fatigue syndrome). Pathogenic mechanisms common among FGIDs may include alternations in intestinal and colonic microora. Evidence is also emerging of an interplay between gut immune cells/activity and alternations in motility, secretion, and sensation. The role of cytokine activity and inammation is important in this regard. As recommended by Rome III, diagnostic testing should be guided by the patients age, primary symptom characteristics, and other clinical and laboratory features. The high prevalence of coexisting conditions suggests the need to routinely assess patients for related disorders. Treatment should be based on an individualized evaluation, explanation, and reassurance. Key Words: irritable, bowel, functional, gastrointestinal, IBS

DIAGNOSING FUNCTIONAL ESOPHAGEAL AND GASTRODUODENAL DISORDERS

It is important to understand the dierent diagnostic criteria for the various functional esophageal and gastroduodenal disorders and for this it is necessary to refer to the current diagnostic criteria as recommended by the 2006 Rome III process.1,10 Functional esophageal disorders include functional heartburn, functional chest pain of esophageal origin, functional dysphagia, and globus. Functional heartburn is dened as episodic retrosternal burning in the absence of gastroesophageal reux disease, histopathology-based motility disorders, or structural disorders. Symptoms are related to acid reux events in the absence of abnormal esophageal acid exposure. In western populations heartburn occurs in 20% to 40% individuals irrespective of sex and age.5 All of the following must be met to meet the diagnostic criteria for functional heartburn: burning retrosternal discomfort or pain; absence of evidence that the gastroesophageal acid reux is the cause of the symptom; absence of a histopathology-based motility disorder. As with all functional esophageal disorders, these criteria must be fullled for 3 months with symptom onset at least 6 months before diagnosis. The diagnostic criteria for functional chest pain of esophageal origin must include all of the following: midline chest pain or discomfort that is not of burning quality; the absence of evidence that gastroesophageal reux is the cause of symptom; and the absence of histopathology-based esophageal motility disorders.10 The diagnostic criteria for functional dysphagia are as follows: sense of solid and/or liquid foods sticking; lodging or passing abnormally through the esophagus; the absence of evidence that gastroesophageal reux is the cause of symptom; and the absence of histopathology-based esophageal motility disorders.10 The diagnostic criteria for globus are the persistant or intermittent, nonpainful sensation of a lump or foreign body in the throat; occurence of the sensation between meals; absence of dysphagia or odynophagia; absence of evidence that gastroesophageal reux is the cause of the symptom; and the absence of histopathology-based esophageal motility disorders.10 Functional gastroduodenal disorders include FD (ie, postprandial distress syndrome (PDS) and epigastric pain syndrome), belching disorders (ie, aerophagia and unspecied excessive belching), nausea and vomiting disorders (ie, chronic nausea, functional vomiting, and cyclic vomiting syndrome), and rumination syndrome. It is useful to note that FD is a heterogeneous disorder associated with diverse pathophysiological mechanisms. PDS must include 1 or more of following: bothersome postprandial fulness, early satiation, epigastric pain, epigastric burning, and no evidence of structural disease that is likely to explain the symptoms (including upper gastrointestinal endoscopy). Diagnostic criteria for PDS include one or both of the J Clin Gastroenterol


(J Clin Gastroenterol 2011;45:S86S88)

rritable bowel syndrome (IBS) is one of several highly prevalent, multisymptom functional gastrointestinal disorders (FGID) that have a wide clinical spectrum and which are associated with symptoms of gastrointestinal dysmotility and visceral hypersensitivity.1 Signicant overlap of symptoms and comorbidities are frequently identied not only between IBS and other FGID [including functional abdominal pain, functional abdominal bloating, functional constipation, functional dyspepsia (FD), and gastroesophageal reux disease], but also with gastrointestinal disorders that are not related to motility (such as celiac disease and lactose intolerance), and to somatic conditions (such as bromyalgia and chronic fatigue syndrome).19 Reecting on whether IBS aects the entire gastrointestinal system, this study considers other related conditions and putatively common pathogenic mechanisms. One clinical implication of coexisting conditions is the need to routinely assess patients for related disorders.

From the Dokuz Eylul University, Medicine Faculty, Department of Gastroenterology, Izmir, Turkey. Supported by Abbott Products Operations AG, Hegenheimermattweg 127, 4123 Allschwil, Switzerland. Conict of Interest: The author is a speaker for Solvay and Abbott and received sponsorships for organizing scientic events from Solvay and Abbott. lkay Sim sek, MD, Dokuz Eylul University, Medicine Reprints: I Faculty, Department of Gastroenterology, Izmir, Turkey (e-mail: ilkay.simsek@deu.edu.tr). Copyright r 2011 by Lippincott Williams & Wilkins

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IBS and Other Functional Gastrointestinal Disorders

following: bothersome postprandial fullness, occuring after ordinary-sized meals, at least several times per week; early satiation that prevents nishing a regular meal, at least several times per week. Supportive criteria including upper abdominal bloating or postprandial nausea or excessive belching can be present; epigastric pain syndrome may coexist. The following must be present for the diagnosis of epigastric pain syndrome: pain or burning localized to the epigastrium at least of moderate severity, at least once per week; pain is intermittent; not generalized or localized to other abdominal or chest regions; not relieved by defecation or passage of atus; not fulllling criteria for gall bladder or sphincter of oddi disorders. Supportive criteria include: the pain may be of a burning quality, but without a retrosternal component; the pain is commonly induced or relieved by ingestion of meal, but may occur while fasting; and PDS may coexist. Interestingly, studies have shown duodenal involvement in the pathophysiology of FD. Patients with FD have shown duodenal hypersensitivity to acid, increased duodenal acid exposure, and abnormal responses to duodenal lipids or released cholecystokinin. Evidence also suggests the involvement of duodenal immune activation in FD. Furthermore, alterations in the number of duodenal eosinophils or intraepithelial lymphocytes have been reported in a subset of patients with FD, particularly those with postinfectious FD.11 Meanwhile, the overlap between FD and IBS was highlighted in an important recent systematic review and meta-analysis. Individuals with dyspepsia were found to have an 8-fold increase in prevalence of IBS compared with the general population, suggesting that dyspeptic patients should be assessed routinely for IBS.9 Among 18,173 individuals included in the analysis, the degree of overlap between the 2 conditions varied from 15% to 42%, depending on diagnostic criteria used for each. Regarding belching disorders, the diagnosis of aerophagia must include all of the following: troublesome repetitive belching at least several times a week; air swallowing that is objectively observed or measured. For unspecied excessive belching: troublesome, repetitive belching at least several times a week; no evidence that excessive air swallowing underlies the symptom. Chronic nausea must include: bothersome nausea occuring at least several times per week; not usually associated with vomiting; absence of abnormalities at upper endoscopy or metabolic disease that explains nausea. Functional vomiting must include: on average 1 or more episodes; absence of criteria for an eating disorder, rumination or major psychiatric disease to DSM-IV; and absence of self-induced vomiting and chronic cannabioid use. There must also be an absence of abnormalities in the central nervous system or metabolic diseases to explain recurrent vomiting. Cyclic vomiting syndrome must include: stereotypical episodes of vomiting regarding onset (acute) and duration (<1 wk); 3 or more discrete episodes in the prior year; and absence of nausea and vomiting between episodes. Supportive criteria include history or family history of migraine headaches.10

IBS PATHOPHYSIOLOGY: BEYOND THE BRAIN-GUT AXIS

Currently, IBS is thought to be a regulation disorder of the so-called brain-gut axis, involving abnormal function in the enteric, autonomic, and/or central nervous systems,
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with peripheral abnormalities probably dominating in some patients and disturbed central processing of signals from the periphery in others.12 The multifactorial pathophysiology of FGID and IBS, therefore encompasses a diverse range of factors that may contribute to altered motility and symptom perception: psychosocial factors (including the possibility of childhood sexual abuse which is associated with a higher incidence of IBS in adulthood13); visceral hypersensitivity; gastrointestinal infection, inammation, or irritation of mucosa; genetics; mast cell involvement suggestive of lowgrade immune activation; food intolerance; and alterations in bacterial ora and luminal antigen.1416 Current theories implicate a number of processes in the development of colonic and small intestinal dysmotility in IBS. These include alternations in transit, abnormal propagation pattern of duodenal contractions, impaired segmental gas handling, and an increase in high-amplitude propagated contractions in the ileum, especially postprandially (mediated by cholecystokinin). Subtle alternations in jejunal migrating motor complex have also been identied that aect phase 3 periodicity and amplitude, phase 2 duration and pattern, and postprandial duration and pattern. The complex role of abnormal bowel ora coupled with the presence of food hypersensitivities on symptom production has been noted in IBS.17 Both food intolerance and altered gut microbial environment may contribute to increased inammation, upregulation of the immune system, altered enteric neurotransmitter output, and abnormal fermentation; all contributing to atulence, pain, bloating, and diarrhea in IBS patients.18 Mildly increased counts of small-bowel bacteria seem to be more common in IBS, although motility alterations could not reliably predict altered small-bowel bacterial ora.19 It has also been shown that gut microbiota may contribute to the onset and maintenance of IBS. In 1 study, quantitative alterations in the gastrointestinal microbiota of IBS patients were found.20 Extensive individual variation was observed in the gastrointestinal microbiota among both the IBS group and control groups. Lower amounts of Lactobacillus species were present in samples of diarrhea-predominant IBS patients, whereas constipation-predominant IBS patients carried increased amounts of Veillonella spp. Dierences in the Clostridium coccoides subgroup and Bidobacterium catenulatum group between IBS patients (n=21) and controls (n=15). It has also been shown that increased enteroendocrine cells, T lymphocytes, and gut permeability represent acute changes after Campylobacter enteritis which can persist for more than a year and may contribute to the development of postdysenteric IBS.21 It is noteworthy that the alteration of intestinal microora is associated with reduction in abdominal bloating and pain in patients with IBS.22 Recently, microarray expression proling has identied relatively stable alterations in colonic mucosal immunity in IBS.23 Twelve upregulated or downregulated genes were identied that are known to be associated with defense against luminal and bacterial antigens, specically relating to mucus protection, the generation of reactive oxygen species, interleukin (IL-1b) processing, and the major histocompatibility complex (MHC-1) antigen processing pathway. These ndings provide the basis to test the hypothesis that objective biomarkers may eventually be identied in IBS. Progress has also been made in our understanding of the mechanisms of visceral hypersensitivity and abdominal www.jcge.com |

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pain in IBS. Intestinal mast cell inltration is thought to participate to abdominal pain in IBS. It is thought that intestinal mast cell inltration may perturb nerve function leading to symptom perception. In a recent study, mucosal mast cell mediators from IBS patients were found to excite rat nociceptive visceral sensory nerves.24 Findings of an earlier clinical study suggested that colonic mast cell inltration and mediator release in proximity to mucosal innervation may contribute to abdominal pain perception in IBS patients (diagnosed according to Rome II criteria).25 In summary, as recommended by Rome III, diagnostic testing should be guided by the patients age, primary symptom characteristics, and other clinical and laboratory features. Treatment of functional bowel disorders is based on an individualized evaluation, explanation, and reassurance. Symptoms of IBS have traditionally been linked to disturbed gastrointestinal motility, visceral hypersensitivity, and psychological distress. However, growing evidence suggests that alternations in intestinal and colonic microora play a role in IBS. Particularly, important in this regard are the observations that infectious gastroenteritis signicantly increases the risk of developing IBS and that quantitave and qualitative changes in gut ora have been noted in IBS patients. Evidence exists for interplay between gut immune cells/activity and alternations in motility, secretion, and sensation. The pathophysiological links between IBS and other FGID continue to be explored and the role of cytokine activity and inammation are emerging areas of research in IBS. REFERENCES
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