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Irritable Bowel Syndrome: How far do you go in the Workup?

Douglas A. Drossman, M.D.
Professor of Medicine and Psychiatry
Co-Director, UNC Center for Functional GI and Motility Disorders
Division of Digestive Diseases
University of North Carolina at Chapel Hill

Address correspondence to:
Douglas A. Drossman, M.D.
Division of Digestive Diseases
726 Burnett-Womack Bldg. CB #7080
University of North Carolina
Chapel Hill, N.C. 27599-7080
Phone: (919) 966-0141
Fax: (919) 966-8929
Email:

The diagnostic evaluation of patients with irritable bowel syndrome (IBS) can be challenging for several reasons. First, there is no biological marker for the disorder. The diagnosis is based primarily on the presence of a clustered set of symptoms relating to abdominal pain or discomfort and altered bowel habit. Second, it follows that a diagnosis based solely on symptoms can be unsettling; clinicians will struggle with the possibility of missing another diagnosis. This level of uncertainty may increase the risk of overdoing diagnostic studies, though many clinicians believe an extensive diagnostic effort justified: it seeks to satisfy the patient's request for a specific diagnosis, as well as the physician's personal interest to "leave no stone unturned". Unfortunately, this approach contributes to the disproportionately high health care costs for IBS relative to other GI disorders as reported in one Health Maintenance Organization study (1). Finally, developing a diagnostic algorithm for IBS can be challenging given the effect of psychosocial co-factors including psychiatric diagnosis, daily and life stress and other psychosocial domains on IBS (2).

Currently, the diagnostic evaluation of patients presenting with IBS symptoms has no simple standard; it is based on the art and science of medicine. Several factors can influence the decision making: a) symptom pattern and severity will influence, for example whether mucosal biopsies are taken for diarrhea-predominant symptoms, or ultrasound or CT are done for pain and weight loss(3), b) demographic features such as older age on initial presentation or a family history of IBD or colon cancer may lead to a more extensive (e.g., colonoscopic) evaluation, c) a patient's pain communication style or illness-related behaviors must be appraised in the light of objective screening data; this, for example will reduce the tendency merely to order tests based on urgent requests to "do something" ("furor medicus") (4), and finally d), the clinical setting will influence the prior probability of other medical disorders; so primary care physicians more than gastroenterologists will minimize diagnostic studies, treat the symptoms of IBS, and follow the patient expectantly (5), simply because the likelihood of another serious medical disease in a primary care setting is far less than in a referral practice.

Efforts to consolidate these many influences on diagnostic decision making have occurred by creating specific published guidelines obtained by consensus (3;6) (7). Most all authors agree that an initial diagnosis of IBS should be fulfilled by: a) meeting symptom-based diagnostic criteria, such as Rome II (6;8), Rome I (9) (10), or occasionally, Manning (11) criteria, obtaining a negative physical examination, and performing a cost-effective, conservative set of screening studies. These usually include a sigmoidoscopy (or colonoscopy for patients older than 50 years), a few laboratory tests (e.g., CBC, stool for occult blood or ova and parasites) and additional studies if certain "alarm" features are found: fever, an abnormal physical examination, blood in the stool, an abnormal CBC or elevated sedimentation rate, significant weight loss, nocturnal symptoms that awaken the patient, or a family history of cancer or inflammatory bowel disease (12;13). Several prospective studies now offer evidence that the proper application of such recommendations rarely leads to a revision in diagnosis, even for patients followed over many years (14;15) (6). In one study, the positive predictive value for the diagnosis of IBS using Rome I criteria and excluding "red flags" over 1-year follow-up was 98% (12).

Of course, the gastroenterologist in referral practice may not be content to accept these probabilities without first excluding those rare conditions overlooked by routine evaluations. So how far should the gastroenterologist go in the workup of patients referred to them who typically present with IBS, and have negative screening studies? One gastroenterologist, recently commented to me: "I order breath hydrogen studies and sprue serologies on all my patients referred with IBS". No doubt this comment reflects the concern that as referral gastroenterologists we have an obligation to contribute additional expertise to the diagnostic effort. Recently, the breath H2 test is being requested more actively by physicians and the public alike possibly because of media attention to a study claiming a 73% rate of bacterial overgrowth in patients with IBS referred for breath H2 testing, and a 50% improvement with antibiotic treatment (16). However, the design limitations of this study, including a high ascertainment bias, use of an uncontrolled and unblinded treatment protocol, and only a 30% follow up rate evaluated over a relatively short period of time, makes it unlikely that clinicians in practice will also obtain such dramatic results. So while this study increases awareness of bacterial overgrowth as an entity that can mimic or exacerbate IBS, clinical experience suggests that the diagnostic yield in general GI practice is probably much lower than reported, perhaps 10% or less.

What about celiac disease? This disorder should always be considered in evaluating IBS, because the diarrhea and abdominal discomfort due to proximal small intestinal villous atrophy and inflammation will specifically respond to a gluten-free diet. Therefore, making a diagnosis early may be cost-effective. The prevalence of celiac disease in the US is reported to range from 1:250 to 1:1500 (17). However, this is influenced by the method of assessment as well as the prior probability of the disorder being present in the population under study. With regard to the method of assessment, in a study set in Olmstead County (18), the reported prevalence was 1:4,600, and the cases were identified by clinical and pathological criteria. In contrast, when serological methods are used, the prevalence is at 1:250 or even higher (19), and in one recent study the prevalence for women was 1:125 compared to males at 1:250 (20). So, when clinically suspected, primary care physicians and specialists may now obtain anti-gliadin and anti-endomysial IgA antibody serologies. These are reasonably effective screening tests, given that the sensitivities and positive predictive values range from 90% - 100% (17). However, in populations where the prevalence of this disorder is low, many positive serological tests will be false positives. Therefore, because the gold standard of diagnosis requires upper endoscopy with duodenal biopsy, endoscopy is almost always needed for confirmation of the diagnosis. But can we be satisfied that these studies are enough to exclude celiac disease?

In this issue of Gastroenterology, Wahnschaffe et al.(21) raise concerns about the possibility of missing a diagnosis of latent or potential celiac disease among persons thought to have IBS. Patients with latent or potential celiac disease have a genetic susceptibility for the disease, but do not have the histopathological findings (i.e., no villous atrophy or notable mucosal inflammation) when exposed to a gluten diet, so a small bowel biopsy will not make this diagnosis. In contrast to potential celiac disease, latent disease is characterized by mucosal changes that occurred at some point in time and recovered on a gluten-free diet. The authors propose that both these groups may still respond clinically to a gluten free diet.

This creative study attempted to identify patients with latent or potential celiac disease (i.e., who presumably had negative serological screens for celiac disease) in a sample of 102 IBS patients. They evaluated a variety of serological, intestinal and genetic markers, and compared the findings to control groups with treated and untreated celiac disease, latent celiac disease and normal controls. They found two surrogate markers: a) the expression of HLA-DQ2 alleles DQA1*050/DQB1*0201, a genetic marker for celiac disease, and b) an increased intestinal IgA titer against tissue-transglutaminase and/or gliadin were elevated in the small sample of patients with latent celiac disease. Notably, the assessment of intestinal (rather than serological) antibodies is a unique aspect of this study; it is a diagnostic method for celiac sprue that is not commonly done. Then, when evaluating the IBS patients, they found that 35% had expression of the HLA-DQ2 genotype, and this subgroup of IBS patients had significantly increased IgA antibodies against the celiac disease-associated antigens gliadin and/or tissue-transglutaminase in the duodenal aspirate, as well as increased intra-epithielial lymphocytes (also characteristic of celiac disease) when compared to IBS patients without expression of the HLA-DQ2 genotype. Furthermore, 26 IBS patients were put on a gluten-free diet for 6 months. The 13 patients who were positive for the HLA-DQ2 alleles and for the intestinal celiac disease-associated antibodies had a significant reduction in stool frequency and intestinal IgA antibody titers for the celiac disease-associated antigens. This improvement did not occur in the remaining IBS patients on gluten free diet who were negative for HLA-DQ2 gene expression. They conclude that the presence of these two markers in patients with IBS may identify a subgroup with latent or potential celiac disease that may respond to dietary restriction.

These findings must be put into a clinical perspective. First, the authors identified the IBS patients as those who had a "…variable combination of abnormal bowel habits in the absence of endoscopic, histopathological, laboratory and microbiological abnormalities." However, these criteria are not sufficient for diagnosing IBS. We do not know how many of these patients actually had abdominal pain, the key symptom criterion for a diagnosis of IBS. Clinically, patients with diarrhea and no pain are considered separate from IBS ("functional diarrhea"), and they define a group where celiac disease is more likely than patients with typical IBS having abdominal pain. In fact, if many of these patients did not have pain, and therefore did not fulfill criteria for IBS, then the findings of the study and its implications for IBS may be quite different. Second, the sample sizes for some of the cells were small. Only 5 patients had latent celiac disease, and the improvement in response to gluten restriction occurred in a sample of 13 patients with IBS who were HLA-DQ2 positive. It will also be valuable to conduct this study in a controlled fashion using a large group of patients with IBS not having celiac disease markers in order to determine the placebo response rate to a gluten free diet. Even the reduction in serologies with a gluten free diet may not provide complete evidence for a clinical response, since dietary restriction of gluten might reduce the antigenic challenge to the immune system, leading to a serological response that is unrelated to the changes in stool frequency. Despite these limitations, this study has raised some important concerns regarding our sense of "security" in accepting normal histopathology to exclude celiac disease in patients having symptoms of IBS, and has opened the door to pursuing these issues in larger clinical trials.

Is it possible that some simple and inexpensive tests will emerge to accurately diagnose IBS? I do not think that IBS can by diagnosed by ordering tests, either to make a unitary diagnosis, or by default by excluding other disorders. There is evidence that IBS is a heterogeneous disorder where different physiological subgroups contribute to the clinical expression of the syndrome. For example, there is a subgroup of patients, called "post-infectious IBS" who appear to respond to an enteric infection such as campylobactor jejuni with an increased inflammatory cell response (22). This is associated with activating enterochromaffin cells to produce 5HT, and CD3 cells to produce cytokines, which in turn leads to enhanced motility and lowered visceral sensation thresholds (22;23). But microscopic inflammation cannot be a diagnostic marker for IBS because it does not typically produce pain in those who have it. All patients with active celiac disease have microscopic inflammation, but a large proportion do not have abdominal pain, and patients with ulcerative colitis who also have microscopic inflammation when compared to patients with IBS appear to have higher pain thresholds (24). In individuals with these disorders, there may be central nervous system counter-regulatory measures responding to the peripheral pain/inflammatory processes that increase pain thresholds.

With regard to IBS, the gut-related effects of microscopic inflammation may be only one component of a dysfunctional brain-gut system. In addition, and often in response to stress, there may be a failure to activate descending pain inhibitory systems that enable the clinical experience of pain and other symptoms that typify this disorder (25). In one prospective study of post-infectious IBS, it was found that those who retained their symptoms 3-months after an enteric infection had not only increased mucosal cellularity, but also had increased psychosocial distress at the time of the infection. Furthermore, lowered visceral sensation thresholds and increased motility were present after the infection regardless of whether or not the patients retained their symptoms (26). Therefore, the microscopic inflammation and its physiological effects on motility and sensation contribute to, but are not always sufficient for the clinical expression of IBS pain. At least for post-infectious IBS this provides some evidence that psychological distress alters brain pain regulatory pathways to amplify incoming visceral signals leading to the full clinical expression of this syndrome (27;28). Recent studies using brain imaging (29;30)may help us to understand the physiological mechanisms that modulate these CNS responses to pain, and in the process, identify the subgroup with IBS that are more amenable to psychological and psychopharmacological treatments. As we continue to develop the means to assess the pathophysiological determinants of IBS symptoms, we will continue to identify subgroups that will change our diagnostic assessment, and may even redefine what we mean by IBS. Post-infectious IBS, and patients having concurrent psychosocial disturbances (among others to be determined) characterize subgroups that will be more responsive to more specific treatments. For the present, we must still make a diagnosis of IBS based on established guidelines including symptom-based (e.g., Rome) criteria. We must also remain vigilant to identifying other relevant disorders like celiac disease that may mimic or exacerbate IBS, and will use clinical judgment (e.g., ordering anti-endomysial antibodies for patients with predominant diarrhea), rather than routinely ordering tests in all IBS patients just to exclude other disease. With careful appraisal of the historical and laboratory data and good clinical judgment, a positive diagnosis of IBS can be made in a cost-effective manner and with confidence.

My thanks to Peter Green, MD for his helpful comments.


Reference List
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