Advances in Functional Bowel Disorders
Advances in Functional Bowel Disorders
New Orleans, Monday, May 17, 2004 -- Over the last several years, irritable bowel syndrome (IBS) has received increasingly intense focus due in part to advances in our knowledge of the socioeconomic impact of the condition, continued development of increasingly effective IBS therapies, increasing public awareness of the disorder, and new understanding regarding the workings of the enteric nervous system. This increased focus was evident from the high volume and quality of IBS-related research presented on Monday, May 17, at Digestive Disease Week. This report highlights some of the more relevant of these sessions.
Epidemiology of IBS
Among patients with IBS, women historically outnumber men by 2-3:1. One study presented during Monday's scientific session examined sex differences with respect to the prevalence of individual diagnostic criteria among patients with confirmed functional gastrointestinal disorders. In this trial of 897 patients, women were more likely to report constipation, bloating, and frequent physician visits over the preceding year, whereas men were more likely to report abdominal pain relieved by defecation or pain associated with a change in stool frequency. These sex-specific differences in the individual symptoms of IBS have important implications when attempting to rely on symptom-based criteria for the diagnosis of IBS as well as for the evolution of future diagnostic criteria.
IBS has been demonstrated to be a major contributor to healthcare and nonhealthcare costs, and it has been noted that the symptoms and diagnosis of IBS are increased in family members of patients with IBS. Levy and colleagues examined the intergenerational transmission of illness behavior among children of 208 mothers diagnosed with IBS compared with children of 241 mothers without IBS. They found that children of mothers with IBS made 50% more health visits and incurred significantly greater healthcare-associated costs than did their comparators. These findings were true for both gastroenterology clinic as well as nongastroenterology visits. They also found that the number of healthcare visits and costs (gastroenterology and nongastroenterology) for the child was directly correlated to the number of healthcare visits and cost (gastroenterology and nongastroenterology) for the mother.
Pathophysiology of IBS
Studies implicating infection as an etiology of IBS have been limited by their retrospective nature, heterogeneous populations, short duration of follow-up, and the diverse infectious agents isolated. Mearin and colleagues reported the results of a year-long analysis of age- and sex-matched populations, half of whom had suffered confirmed infection with Salmonella enteritidis on the same day in 2002. At 3-, 6-, and 12-month symptom follow-up (based on Rome II criteria), the group infected with Salmonella were significantly more likely than controls to fulfill symptom-based criteria for IBS, with a relative risk of 14.8 at 1 year compared with controls.
The concept of somatic and visceral hypersensitivity also garnered significant attention during this year's meeting. In a small study of functional magnetic resonance imaging (fMRI), patients with IBS demonstrated significantly greater deactivation of the limbic and cingulate regions in response to emotionally distressing stimuli, suggesting that previously observed differences in central nervous system stimulus processing may not be specific for visceral sensation but may be more generalized. Simren and colleagues evaluated the presence of visceral hypersensitivity in several groups of patients with IBS from a variety of referral settings to test the hypothesis that patients from tertiary care -- theoretically the patients with the most severe or refractory symptoms -- demonstrate more visceral hypersensitivity than patients with IBS from primary-care settings or patients with IBS who were nonconsulters. They showed that regardless of referral setting, patients with IBS demonstrated similar degrees of visceral hypersensitivity compared with healthy controls. Additionally, there does not appear to be a significant difference in visceral hypersensitivity among IBS patients from different referral settings. The role of these findings in routine clinical practice remains to be seen.
Diagnosis of IBS
Therapy for IBS symptoms is typically predicated on identifying the predominant symptom complex that the patient is experiencing. Historically, patients will fall into 1 of 3 broad categories: those with IBS with constipation (IBS-C), those with IBS with diarrhea (IBS-D), and those with alternating symptoms. The Rome II criteria differentiate between patients with diarrhea or constipation, but do not define alternators. This is clinically important because the embarkation on 1 therapeutic regimen based on predominant symptoms may, as symptoms change in alternators, result in accelerating symptoms to the other extreme. Several studies presented during this year's scientific session evaluated the identification of patients with alternating IBS symptoms.
Pimental and colleagues used a previously validated symptom severity score measuring abdominal pain, diarrhea, and constipation on a 5-point visual analogue scale and were able to confidently differentiate between patients with IBS-C, IBS-D, and alternators. Whitehead and colleagues, using different symptom-based criteria, determined that approximately 50% of patients with IBS reported alternating bowel habits and that these patients were more likely to report more severe symptoms, psychological distress, and impaired quality of life than were nonalternators.
There are some data to suggest that undiagnosed celiac sprue may be a confounder in patients with IBS symptoms, and therefore some experts suggest that patients with IBS symptoms should routinely be tested for celiac disease. Spiegel and colleagues performed a decision analysis of the cost-effectiveness of serologic and endoscopic testing for celiac disease in IBS vs empiric IBS therapy. Testing for celiac disease was the dominant strategy when the prevalence of celiac disease was greater than 8%, when the specificity of celiac disease testing was greater than 98%, or when the cost of IBS care was greater than $130 per month. Testing for celiac disease had an acceptable degree of cost-effectiveness when the prevalence of sprue exceeded 1%. Prospective clinical data are needed regarding this issue.
Natural History of IBS
The natural history of IBS is not well understood. Talley and colleagues reported the results of an ongoing study measuring the prevalence of functional gastrointestinal disorders in a single population over time. Previous surveys of this population have demonstrated stable prevalence rates of IBS overall but significant variability in the patients reporting symptom onset or regression. This current survey, conducted in 2003, demonstrates again that symptom change is common, but that functional disorders may not be as chronic in individual patients as previously thought.
Several studies reported on the incidence of abdominal surgeries and ischemic colitis in patients with IBS. In a well-done analysis, Cole and colleagues determined that patients with IBS are 3 times more likely to undergo gallbladder surgery and twice as likely to undergo any abdominal surgery compared with non-IBS patients. These findings echo previous reports. Singh and colleagues examined the incidence of ischemic colitis in a large representative population of patients with IBS and found, similar to findings in recent reports, a 3-fold increased risk of ischemic colitis among IBS patients relative to non-IBS controls. These findings have important implications for future IBS therapy trials and should be kept in mind when considering adverse events associated with various therapies.
Therapeutic Options in IBS
One relative constant in therapy trials of functional gastrointestinal disorders is the relatively high placebo response rate. In a meta-analysis presented during this year's meeting, Patel and coworkers determined that placebo response rate in clinical IBS trials ranged from 16% to 71% with an average of 44%, and that the main predictor of placebo variability was the presence of invasive procedures as part of the protocol. Other factors, such as study methodology parameters and number of office visits, did not appear to play a significant role in the placebo response.
A recent large study included desipramine in one of the treatment arms and reaffirmed the effectiveness of tricyclic antidepressants for some patients with IBS. One criticism of this trial, however, was that there appeared to be a sizable discontinuation rate of tricyclic antidepressants secondary to adverse events. Based on additional data from this trial, Dalton and colleagues were able to demonstrate that patients taking tricyclic antidepressants were more likely to report certain somatic symptoms even before they began tricyclic antidepressant therapy. Fatigue, nausea, blurred vision, and difficulty sleeping were all reported more commonly by these patients before and after tricyclic antidepressant therapy.
Several studies addressing serotonergic agents for IBS were also presented during these meeting proceedings. Di Stefano and colleagues demonstrated that improvements in bloating achieved with tegaserod do not appear to be due to decreases in gas production or changes in rectal sensitivity. They hypothesized that such improvements may stem from promotility effects of the drug. Bradette and colleagues reported the results of a large (N = 792) study comparing 6 months of cilansetron (a 5-HT3 antagonist) 2 mg thrice daily vs placebo in men and women with IBS-D. Overall, results were promising, with a therapeutic gain for cilansetron over placebo of 15% to 20% at months 1-3 as well as at the end of 6 months. Contrary to previous reports with similar agents, these results were consistent across sexes. One note of caution is due regarding the occurrence of 3 episodes of self-limited suspected ischemic colitis in the cilansetron group; additional investigation is warranted to assess its significance.
Concluding Remarks
IBS continued to generate a great deal of high-quality research as efforts persist to unravel its pathophysiology and to optimize patient care. Significant advances in epidemiology, brain-gut interactions, diagnosis, and treatment continue to push the science forward in this field.
References
New Orleans, Monday, May 17, 2004 -- Over the last several years, irritable bowel syndrome (IBS) has received increasingly intense focus due in part to advances in our knowledge of the socioeconomic impact of the condition, continued development of increasingly effective IBS therapies, increasing public awareness of the disorder, and new understanding regarding the workings of the enteric nervous system. This increased focus was evident from the high volume and quality of IBS-related research presented on Monday, May 17, at Digestive Disease Week. This report highlights some of the more relevant of these sessions.
Epidemiology of IBS
Among patients with IBS, women historically outnumber men by 2-3:1. One study presented during Monday's scientific session examined sex differences with respect to the prevalence of individual diagnostic criteria among patients with confirmed functional gastrointestinal disorders. In this trial of 897 patients, women were more likely to report constipation, bloating, and frequent physician visits over the preceding year, whereas men were more likely to report abdominal pain relieved by defecation or pain associated with a change in stool frequency. These sex-specific differences in the individual symptoms of IBS have important implications when attempting to rely on symptom-based criteria for the diagnosis of IBS as well as for the evolution of future diagnostic criteria.
IBS has been demonstrated to be a major contributor to healthcare and nonhealthcare costs, and it has been noted that the symptoms and diagnosis of IBS are increased in family members of patients with IBS. Levy and colleagues examined the intergenerational transmission of illness behavior among children of 208 mothers diagnosed with IBS compared with children of 241 mothers without IBS. They found that children of mothers with IBS made 50% more health visits and incurred significantly greater healthcare-associated costs than did their comparators. These findings were true for both gastroenterology clinic as well as nongastroenterology visits. They also found that the number of healthcare visits and costs (gastroenterology and nongastroenterology) for the child was directly correlated to the number of healthcare visits and cost (gastroenterology and nongastroenterology) for the mother.
Pathophysiology of IBS
Studies implicating infection as an etiology of IBS have been limited by their retrospective nature, heterogeneous populations, short duration of follow-up, and the diverse infectious agents isolated. Mearin and colleagues reported the results of a year-long analysis of age- and sex-matched populations, half of whom had suffered confirmed infection with Salmonella enteritidis on the same day in 2002. At 3-, 6-, and 12-month symptom follow-up (based on Rome II criteria), the group infected with Salmonella were significantly more likely than controls to fulfill symptom-based criteria for IBS, with a relative risk of 14.8 at 1 year compared with controls.
The concept of somatic and visceral hypersensitivity also garnered significant attention during this year's meeting. In a small study of functional magnetic resonance imaging (fMRI), patients with IBS demonstrated significantly greater deactivation of the limbic and cingulate regions in response to emotionally distressing stimuli, suggesting that previously observed differences in central nervous system stimulus processing may not be specific for visceral sensation but may be more generalized. Simren and colleagues evaluated the presence of visceral hypersensitivity in several groups of patients with IBS from a variety of referral settings to test the hypothesis that patients from tertiary care -- theoretically the patients with the most severe or refractory symptoms -- demonstrate more visceral hypersensitivity than patients with IBS from primary-care settings or patients with IBS who were nonconsulters. They showed that regardless of referral setting, patients with IBS demonstrated similar degrees of visceral hypersensitivity compared with healthy controls. Additionally, there does not appear to be a significant difference in visceral hypersensitivity among IBS patients from different referral settings. The role of these findings in routine clinical practice remains to be seen.
Diagnosis of IBS
Therapy for IBS symptoms is typically predicated on identifying the predominant symptom complex that the patient is experiencing. Historically, patients will fall into 1 of 3 broad categories: those with IBS with constipation (IBS-C), those with IBS with diarrhea (IBS-D), and those with alternating symptoms. The Rome II criteria differentiate between patients with diarrhea or constipation, but do not define alternators. This is clinically important because the embarkation on 1 therapeutic regimen based on predominant symptoms may, as symptoms change in alternators, result in accelerating symptoms to the other extreme. Several studies presented during this year's scientific session evaluated the identification of patients with alternating IBS symptoms.
Pimental and colleagues used a previously validated symptom severity score measuring abdominal pain, diarrhea, and constipation on a 5-point visual analogue scale and were able to confidently differentiate between patients with IBS-C, IBS-D, and alternators. Whitehead and colleagues, using different symptom-based criteria, determined that approximately 50% of patients with IBS reported alternating bowel habits and that these patients were more likely to report more severe symptoms, psychological distress, and impaired quality of life than were nonalternators.
There are some data to suggest that undiagnosed celiac sprue may be a confounder in patients with IBS symptoms, and therefore some experts suggest that patients with IBS symptoms should routinely be tested for celiac disease. Spiegel and colleagues performed a decision analysis of the cost-effectiveness of serologic and endoscopic testing for celiac disease in IBS vs empiric IBS therapy. Testing for celiac disease was the dominant strategy when the prevalence of celiac disease was greater than 8%, when the specificity of celiac disease testing was greater than 98%, or when the cost of IBS care was greater than $130 per month. Testing for celiac disease had an acceptable degree of cost-effectiveness when the prevalence of sprue exceeded 1%. Prospective clinical data are needed regarding this issue.
Natural History of IBS
The natural history of IBS is not well understood. Talley and colleagues reported the results of an ongoing study measuring the prevalence of functional gastrointestinal disorders in a single population over time. Previous surveys of this population have demonstrated stable prevalence rates of IBS overall but significant variability in the patients reporting symptom onset or regression. This current survey, conducted in 2003, demonstrates again that symptom change is common, but that functional disorders may not be as chronic in individual patients as previously thought.
Several studies reported on the incidence of abdominal surgeries and ischemic colitis in patients with IBS. In a well-done analysis, Cole and colleagues determined that patients with IBS are 3 times more likely to undergo gallbladder surgery and twice as likely to undergo any abdominal surgery compared with non-IBS patients. These findings echo previous reports. Singh and colleagues examined the incidence of ischemic colitis in a large representative population of patients with IBS and found, similar to findings in recent reports, a 3-fold increased risk of ischemic colitis among IBS patients relative to non-IBS controls. These findings have important implications for future IBS therapy trials and should be kept in mind when considering adverse events associated with various therapies.
Therapeutic Options in IBS
One relative constant in therapy trials of functional gastrointestinal disorders is the relatively high placebo response rate. In a meta-analysis presented during this year's meeting, Patel and coworkers determined that placebo response rate in clinical IBS trials ranged from 16% to 71% with an average of 44%, and that the main predictor of placebo variability was the presence of invasive procedures as part of the protocol. Other factors, such as study methodology parameters and number of office visits, did not appear to play a significant role in the placebo response.
A recent large study included desipramine in one of the treatment arms and reaffirmed the effectiveness of tricyclic antidepressants for some patients with IBS. One criticism of this trial, however, was that there appeared to be a sizable discontinuation rate of tricyclic antidepressants secondary to adverse events. Based on additional data from this trial, Dalton and colleagues were able to demonstrate that patients taking tricyclic antidepressants were more likely to report certain somatic symptoms even before they began tricyclic antidepressant therapy. Fatigue, nausea, blurred vision, and difficulty sleeping were all reported more commonly by these patients before and after tricyclic antidepressant therapy.
Several studies addressing serotonergic agents for IBS were also presented during these meeting proceedings. Di Stefano and colleagues demonstrated that improvements in bloating achieved with tegaserod do not appear to be due to decreases in gas production or changes in rectal sensitivity. They hypothesized that such improvements may stem from promotility effects of the drug. Bradette and colleagues reported the results of a large (N = 792) study comparing 6 months of cilansetron (a 5-HT3 antagonist) 2 mg thrice daily vs placebo in men and women with IBS-D. Overall, results were promising, with a therapeutic gain for cilansetron over placebo of 15% to 20% at months 1-3 as well as at the end of 6 months. Contrary to previous reports with similar agents, these results were consistent across sexes. One note of caution is due regarding the occurrence of 3 episodes of self-limited suspected ischemic colitis in the cilansetron group; additional investigation is warranted to assess its significance.
Concluding Remarks
IBS continued to generate a great deal of high-quality research as efforts persist to unravel its pathophysiology and to optimize patient care. Significant advances in epidemiology, brain-gut interactions, diagnosis, and treatment continue to push the science forward in this field.
References
Hammer J, Talley NJ. Gender differences in functional bowel disorders. Gastroenterology. 2004;126(suppl 2):A-375. [M1642]
Levy RL, Whitehead WE, Walker L, et al. Impact of learned behavior on health care costs. Gastroenterology. 2004;126(suppl 2):A-28. [Abstract 247]
Mearin F, Perez-Oliveras M, Perello A, et al. Irritable bowel syndrome after salmonella gastroenteritis: one year follow-up prospective cohorts study. Gastroenterology. 2004;126(suppl 2):A-372. [M1628]
Andresen V, Tsrouya C, Bach D, et al. Altered limbic response patterns to auditory stimuli in patients with irritable bowel Syndrome (IBS) generalized changes of emotional stimulus-processing. Gastroenterology. 2004;126(suppl 2):A-28. [Abstract 249]
Simren M, Ringstrom G, Lindh A, et al. Is rectal hypersensitivity in irritable bowel syndrome (IBS) only present in tertiary care patients? Gastroenterology. 2004;126(suppl 2):A-368. [M1610]
Pimental M, Park S, Kong Y. Testing a definition of predominantly alternating bowel habits in IBS using the previously validated Rome composite score (RCS) questionnaire. Gastroenterology. 2004;126(suppl 2):A-373. [M1637]
Whitehead WE, Palsson OS, Levy RL, et al. Identification of irritable bowel (IBS) patients with alternating bowel habits. Gastroenterology. 2004;126(suppl 2):A-369. [M1616]
Spiegel BMR, DeRosa VP, Gralnek IM, et al. Is it worth testing for celiac sprue in irritable bowel syndrome? A cost-effectiveness analysis. Gastroenterology. 2004;126(suppl 2):A-37. [Abstract 328]
Talley NJ, Locke GR, Schleck CD, et al. Natural history of functional GI disorders: a population-based study 1988-2003. Gastroenterology. 2004;126(suppl 2):A-369. [M1618]
Cole JA, Sherman JM, Earnest DL, et al. The risk of abdominopelvic surgery is increased among patients with irritable bowel syndrome. Gastroenterology. 2004;126(suppl 2):A-374. [M1640]
Singh G, Mithal A, Triadafilopoulos G. Patients with irritable bowel syndrome have a high-risk of developing ischemic colitis. Gastroenterology. 2004;126(suppl 2):A-41. [Abstract 349]
Patel SM, Ock SM, Stason W, et al. The placebo effect in irritable bowel syndrome (IBS) trials: a meta-analysis. Gastroenterology. 2004;126(suppl 2):A-369. [M1614]
Dalton C, Diamant NE, Morris CB, et al. Are side effects of tricyclic antidepressants (TCAs) really side effects? Gastroenterology. 2004;126(suppl 2):A-28. [Abstract 250]
Di Stefano M, Missanelli A, Miceli E, et al. Tegaserod improves abdominal bloating without modifying intestinal gas production capacity. Gastroenterology. 2004;126(suppl 2):A-378. [M1661]
Bradette M, Moennikes H, Carter F, et al. Cilansetron in irritable bowel syndrome with diarrhea predominance (IBS-D): efficacy and safety in a 6 month global study. Gastroenterology. 2004;126(suppl 2):A-42. [Abstract 351]
