Functional GI Disorders -- An Expert Interview With William D. Chey, MD
Editor's Note:

Broadly defined, the functional gastrointestinal disorders are characterized by the presence of symptoms referable to the gastrointestinal tract in the absence of a currently recognized biochemical or structural explanation. Indeed, evidence suggests that health-related quality of life is more impaired in patients with functional gastrointestinal disorders. Therapeutic strategies need to target not only changes in disease activity, but also patients' overall well-being and burden of illness. Medscape spoke with William D. Chey, MD, AGAF, FACG, Professor of Medicine, Division of Gastroenterology, University of Michigan Health System, Ann Arbor, Michigan, to discuss the latest thinking regarding these clinically important disorders, as framed by data presented during the 2007 annual meeting of the American College of Gastroenterology (ACG).

Medscape: Let's begin by talking a little about esophageal sensation in nonerosive reflux disease (NERD) and functional heartburn. The association between serum cortisol levels and visceral pain has varied considerably in reported studies. At this year's ACG meeting, Rodriguez-Stanley and colleagues reported their findings on the correlation between serum cortisol and maximum tolerable pain to balloon distention of the esophagus in patients with NERD and functional heartburn. What can you tell us about this study, and what were the key findings?

Dr. Chey: There is growing evidence to suggest that the hypothalamic-pituitary adrenal axis may play a role in functional gastrointestinal disorders. For example, exogenous administration of corticotrophin-releasing hormone has been reported to induce exaggerated motor responses and abdominal discomfort in patients with IBS.

At this year's ACG meeting, Rodriguez-Stanley and colleagues reported on the association between serum cortisol, adrenocorticotropic hormone levels, and esophageal sensation thresholds for balloon distention in 26 patients with functional heartburn (n = 14) and NERD (n = 12). They found a statistically significant inverse correlation between serum cortisol and the pressure needed to induce maximum tolerated distention (r = 0.50, P = .0001), and a significant positive relationship between adrenocorticotropic hormone levels and cortisol. Because high serum cortisol levels were associated with lower pain thresholds to esophageal balloon distention, they concluded that adrenal function may play a role in functional gastrointestinal disorders.

Because the functional heartburn patients underwent studies on 4 different occasions, it is impossible to know whether the authors' findings were the consequence of exaggerated anticipatory responses to the repeated induction of chest pain or truly the consequence of the patient's underlying disease state. Regardless, this study adds to the growing literature drawing an association between adrenal function and visceral sensation. and begs the question of whether corticotropin-releasing hormone antagonists might represent a treatment option for functional gastrointestinal disorders. One also wonders whether altered hypothalamic-pituitary adrenal axis function might provide a rationale for recent reports of visceral hypersensitivity to esophageal balloon distention and more severe heartburn in gastroesophageal reflux disease patients with comorbid psychological distress.

Medscape: Chronic constipation is an extremely prevalent condition that poses considerable challenges to the treating physician. Indeed, approximately 2% of the US population describes constant or frequent intermittent episodes of constipation. During this year's meeting, Shahid and colleagues looked at the wide range of colonic motor disorders that may exist among individuals presenting with a primary complaint of chronic constipation. Can you briefly discuss these findings and their clinical relevance?

Dr. Chey: Shahid and colleagues reported on a retrospective analysis of 212 patients with chronic constipation who underwent detailed structural and functional testing (anorectal manometry, balloon expulsion testing, whole gut scintigraphy, anal electromyography, and defecography) at Temple University Hospital Motility Center between 2001 and 2006. On the basis of this detailed evaluation, they reported that 43% of patients had slow transit constipation, 12% had dyssynergic defecation, and 20% had a combination of slow transit constipation and dyssynergic defecation. These findings are similar to those of reports from other tertiary referral centers. Some variance in results from center to center is to be expected given differences in patient populations and the lack of standardization for performing or interpreting the results of these tests.

Perhaps of greater interest was that 30% of constipated patients in the Temple series had evidence of delayed gastric emptying, 11% had delayed small bowel transit, and 11% had both delayed gastric emptying and small bowel transit. The finding that over 50% of patients had evidence of delayed transit involving the upper gastrointestinal tract underscores that many constipated patients likely suffer from a diffuse neuroenteric and/or motor disorder rather than a condition isolated to the colon. Furthermore, these results provide a physiologic rationale for the tremendous upper and lower gastrointestinal symptom overlap reported in patients with chronic constipation, and reinforce the need for detailed testing of upper and lower gastrointestinal tract function prior to proceeding with subtotal colectomy in patients with slow transit constipation. Finally, this study and others like it challenge our current scheme of separating patients with functional gastrointestinal symptoms into distinct and separate symptom-based buckets (ie, functional heartburn, functional dyspepsia, irritable bowel syndrome, chronic constipation).

Medscape: Anorectal manometry has been considered the gold standard for the diagnosis of dyssynergic defecation, a common form of functional constipation. However, this diagnostic study is not widely available and there is also a lack of standardization. In this context, Rao and colleagues presented the results of a study assessing the diagnostic utility of digital rectal examination in patients with constipation and difficult defecation. What can you tell us about the study findings, and what are the potential implications?

Dr. Chey: Primary care physicians, and many gastroenterologists, are uncomfortable making the diagnosis of outlet obstruction constipation or dyssynergic defecation. The ability to correctly diagnose dyssynergic defecation is critical because affected patients often will not have improvement in their symptoms with standard laxative therapy. In fact, for severely affected patients, physical therapy and biofeedback training is the treatment of choice.

Most experts have advocated anorectal manometry, balloon expulsion testing, and/or defecography as the optimal means by which to arrive at a diagnosis of dyssynergic defecation. Unfortunately, these tests are not widely available, and even where available, methodology and interpretation of results have not been standardized. When attempting to make a diagnosis of dyssynergic defecation, my suspicion is that most physicians do not recognize the value of a dedicated perianal and digital rectal examination. Although there is literature to support the value of digital rectal examination in patients with fecal incontinence, there are essentially no studies that have addressed the role of this technique in patients with dyssynergic defecation. Rao and colleagues attempted to perform such an analysis and assessed the diagnostic yield of digital rectal examination in patients with constipation and difficult defecation. Their retrospective review of 100 patients evaluated by a single experienced gastroenterologist found that a detailed digital rectal examination (anocutaneous reflex, resting and squeeze anal sphincter pressures, perineal descent, and anal relaxation with straining) yielded a sensitivity and positive predictive value for dyssynergic defecation of 81% and 99%, respectively, when compared with anorectal manometry. Of course, it is impossible to know whether these impressive numbers for digital rectal examination can be reproduced by community physicians or even other "experts." It will be interesting to see if other centers can reproduce these results. Moreover, it would have been interesting to know the negative predictive value of digital rectal examination for dyssynergic defecation. From a practical standpoint, it would be reassuring to know that a normal digital rectal examination excludes dyssynergic defecation. A properly designed prospective study in constipated patients with and without dyssynergic defecation, preferably linked to clinical outcomes following appropriate medical or behavioral therapies, is clearly warranted.

For now, it seems clear that greater emphasis should be placed on teaching gastroenterologists how to properly perform a digital rectal examination. Dedicated teaching of this very important part of the physical examination needs to be incorporated into the training of all gastroenterology fellows.

Medscape: Determination of colonic transit time has a role in the evaluation of the patient with chronic constipation. This is accomplished by observing the passage of orally administered radiopaque markers on abdominal x-ray. However, there are limitations associated with this technique, including unclear gender effects, complex regimens, compliance issues, and limited normative data. In this setting, Rao and colleagues investigated the utility of a wireless pH and pressure recording capsule in assessing colonic transit time. Can you briefly discuss the key findings of this study, with a view toward the implications for clinical practice?

Dr. Chey: Most experts recommend that patients with typical constipation symptoms and no alarm features can be treated with dietary/lifestyle recommendations and empiric medical therapy. Unfortunately, a significant proportion of constipated patients will not respond adequately to these interventions. In such a circumstance, more detailed diagnostic evaluation can help to define the etiology of a patient's constipation. We have already discussed the importance of an adequate digital rectal examination and in some cases anorectal manometry, balloon expulsion testing, and/or defecography to identify dyssynergic defecation. Colonic transit is typically evaluated using radiopaque markers. These radiopaque markers, using a single 5-day film, provide a validated means of assessing colon transit. Unfortunately, these diagnostic studies provide only a qualitative assessment (normal or abnormal) of colon transit, require 2 separate visits, and are associated with radiation exposure. Additionally, radiopaque marker studies do not allow regional gastrointestinal transit determinations, which may have relevance in patients with overlapping upper and lower gastrointestinal symptoms. The most graphic illustration of this issue pertains to patients with medically refractory constipation who are being considered for subtotal colectomy. In such patients, it is routine to order a radiopaque marker study to establish the presence of delayed colonic transit. In addition, many experts would suggest that gastric scintigraphy be performed to exclude the presence of delayed gastric emptying, which appears to be a predictor of poorer clinical outcome following colectomy. Although not evidence based, many surgeons and gastroenterologists also have a low threshold to order a small bowel follow-through to provide a rough assessment of small bowel transit. Of course, each incremental test is associated with more time, inconvenience, radiation exposure, and cost to the patient.

Thus, a simple, standardized nonradioactive technique that could provide whole gut and regional transit information would be a welcome addition to the diagnostic armamentarium of gastroenterologists and GI surgeons. A wireless capsule that records pH, contractile activity, and temperature offers a potential solution to many of these issues. Recent work demonstrated a good correlation between gastric emptying results yielded by scintigraphy and the wireless pH/motility capsule in patients with a history of gastroparesis. During this year's ACG meeting, Rao and colleagues reported a correlation between the wireless pH/motility capsule and the percentage of radiopaque markers expelled on day 2 (r = 0.72, P < .001) and day 5 (r = 0.54, P < .001) in 70 healthy volunteers. This study provides some of the first evidence that this new technology may be useful as a means of assessing small bowel and colon transit as well as gastric emptying. Moreover, it provides one of the largest datasets on normal colon transit as measured by the radiopaque marker technique, which should prove useful for clinicians employing this test in their practices.

Validation of the accuracy of this wireless capsule in patients with abnormalities in colon transit is necessary. Furthermore, this technique provides information regarding motility, which at present is of unclear clinical value. In fact, motility/pH capsule technology allows the opportunity to look at several parameters of function that might hold relevance in the care of patients with a number of gastrointestinal symptom complexes. In the short term, this technique could revolutionize the way pharmacodynamic transit studies with novel drugs are performed. Only time and more appropriately designed studies will determine the place of this capsule in the management of patients with constipation, dyspepsia, bloating, small intestinal bacterial overgrowth, and irritable bowel syndrome.

Supported by independent educational grants from Abbott and Shire