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Diagnosis, Comorbidities, and Management of Irritable Bowel Syndrome in Patients in a Large Health Maintenance Organization

Published:August 25, 2011DOI:https://doi.org/10.1016/j.cgh.2011.08.015

      Background & Aims

      Irritable bowel syndrome (IBS) imposes significant clinical and economic burdens. We aimed to characterize practice patterns for patients with IBS in a large health maintenance organization, analyzing point of diagnosis, testing, comorbidities, and treatment.

      Methods

      Members of Kaiser Permanente Northern California who were diagnosed with IBS were matched to controls by age, sex, and period of enrollment. We compared rates of testing, comorbidities, and interventions.

      Results

      From 1995–2005, IBS was diagnosed in 141,295 patients (mean age, 46 years; standard deviation, 17 years; 74% female). Internists made 68% of diagnoses, gastroenterologists 13%, and others 19%. Lower endoscopy did not usually precede IBS diagnosis. Patients with IBS were more likely than controls to have blood, stool, endoscopic, and radiologic tests and to undergo abdominal or pelvic operations (odds ratios, 1.5–10.7; all P < .0001). Only 2.7% were tested for celiac disease, and only 1.8% were eventually diagnosed with inflammatory bowel disease. Chronic pain syndromes, anxiety, and depression were more common among IBS patients than among controls (odds ratios, 2.7–4.6; all P < .0001). Many patients with IBS were treated with anxiolytics (61%) and antidepressants (55%). Endoscopic and radiologic testing was most strongly associated with having IBS diagnosed by a gastroenterologist. Psychotropic medication use was most strongly associated with female sex.

      Conclusions

      In a large, managed care cohort, most diagnoses of IBS were made by generalists, often without endoscopic evaluation. Patients with IBS had consistently higher rates of testing, chronic pain syndromes, psychiatric comorbidity, and operations than controls. Most patients with IBS were treated with psychiatric medications.

      Keywords

      Abbreviations used in this paper:

      CI (confidence interval), IBS (irritable bowel syndrome), KPNC (Kaiser Permanente Northern California), OR (odds ratio), SD (standard deviation), SSRI (selective serotonin reuptake inhibitor), TCA (tricyclic antidepressant)
      Irritable bowel syndrome (IBS) affects between 10% and 20% of the U.S. population and accounts for $1.6 billion in direct and $19.2 billion in indirect costs annually.
      • Spiegel B.M.
      The burden of IBS: looking at metrics.
      • Sandler R.S.
      • Everhart J.E.
      • Donowitz M.
      • et al.
      The burden of selected digestive diseases in the United States.
      • Longstreth G.F.
      • Thompson W.G.
      • Chey W.D.
      • et al.
      Functional bowel disorders.
      IBS is a symptom-based diagnosis, and concepts about the appropriate investigation in patients with suspected IBS have evolved over time. For example, celiac disease has been recognized in a minority of patients with IBS, and recent guidelines on the diagnosis and treatment of IBS recommend a limited diagnostic work-up including screening for celiac disease.
      • Ford A.C.
      • Chey W.D.
      • Talley N.J.
      • et al.
      Yield of diagnostic tests for celiac disease in individuals with symptoms suggestive of irritable bowel syndrome: systematic review and meta-analysis.
      • Jadallah K.A.
      • Khader Y.S.
      Celiac disease in patients with presumed irritable bowel syndrome: a case-finding study.
      • Zwolińska-Wcisło M.
      • Galicka-Latała D.
      • Rozpondek P.
      • et al.
      [Frequency of celiac disease and irritable bowel syndrome coexistance and its influence on the disease course].
      • Cash B.D.
      • Schoenfeld P.
      • Chey W.D.
      The utility of diagnostic tests in irritable bowel syndrome patients: a systematic review.
      • Korkut E.
      • Bektas M.
      • Oztas E.
      • et al.
      The prevalence of celiac disease in patients fulfilling Rome III criteria for irritable bowel syndrome.
      • Spiller R.
      • Aziz Q.
      • Creed F.
      • et al.
      Guidelines on the irritable bowel syndrome: mechanisms and practical management.
      • Brandt L.J.
      • Chey W.D.
      • Foxx-Orenstein A.E.
      • et al.
      An evidence-based position statement on the management of irritable bowel syndrome.
      IBS treatment remains challenging, with few directed therapies available. Numerous studies suggest a potential role for antidepressants in IBS treatment.
      • Halpert A.
      • Dalton C.B.
      • Diamant N.E.
      • et al.
      Clinical response to tricyclic antidepressants in functional bowel disorders is not related to dosage.
      • Ford A.C.
      • Talley N.J.
      • Schoenfeld P.S.
      • et al.
      Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and meta-analysis.
      • Drossman D.A.
      • Toner B.B.
      • Whitehead W.E.
      • et al.
      Cognitive-behavioral therapy versus education and desipramine versus placebo for moderate to severe functional bowel disorders.
      • Ladabaum U.
      • Sharabidze A.
      • Levin T.R.
      • et al.
      Citalopram provides little or no benefit in nondepressed patients with irritable bowel syndrome.
      • Talley N.J.
      • Kellow J.E.
      • Boyce P.
      • et al.
      Antidepressant therapy (imipramine and citalopram) for irritable bowel syndrome: a double-blind, randomized, placebo-controlled trial.
      • Friedrich M.
      • Grady S.E.
      • Wall G.C.
      Effects of antidepressants in patients with irritable bowel syndrome and comorbid depression.
      • Rahimi R.
      • Nikfar S.
      • Rezaie A.
      • et al.
      Efficacy of tricyclic antidepressants in irritable bowel syndrome: a meta-analysis.
      Practice patterns in the community relating to the diagnosis and management of IBS are not well-described. The extent to which IBS is diagnosed by generalists as opposed to specialists and the reliance on invasive tests such as endoscopy to rule out other diseases are not well-characterized. Several studies have highlighted that patients with IBS undergo more diagnostic testing and operations than their non-IBS counterparts,
      • Longstreth G.F.
      Avoiding unnecessary surgery in irritable bowel syndrome.
      • Longstreth G.F.
      • Yao J.F.
      Irritable bowel syndrome and surgery: a multivariable analysis.
      • Lu C.L.
      • Liu C.C.
      • Fuh J.L.
      • et al.
      Irritable bowel syndrome and negative appendectomy: a prospective multivariable investigation.
      • Johannson A.
      • Farup G.
      • Bracco A.
      • et al.
      How does comorbidity affect cost of health care in patients with irritable bowel syndrome? A cohort study in general practice.
      • Spiegel B.
      • Kanwal F.
      • Naliboff B.
      • et al.
      The impact of somatization on the use of gastrointestinal health-care resources in patients with irritable bowel syndrome.
      but detailed accounting across the spectrum of care is usually not available. Although both psychiatric comorbidity in IBS and the potential benefit of antidepressants in nondepressed IBS patients are well-recognized, it is not clear to what extent psychotropic medications are used in IBS patients in general practice.
      Our aims were to characterize practice patterns relating to the diagnosis and management of IBS in community practice, with attention to point of diagnosis and associated tests, comorbidities, and medication use. We performed an observational study of persons diagnosed with IBS and controls without an IBS diagnosis in Kaiser Permanente Northern California (KPNC), a large health maintenance organization.

      Materials and Methods

       General Study Design

      In this large observational study, we investigated practice patterns associated with the diagnosis and management of IBS and comorbidities associated with IBS in members of KPNC. Medical databases were searched to identify subjects who received a diagnosis of IBS. Controls were matched by age, gender, and length and time of insurance coverage by KPNC. Databases were queried to determine group demographics, medical visits and testing, comorbidities, medication use, and surgical interventions. The University of California San Francisco Committee of Human Research and the KPNC Institutional Review Board approved the study.

       Aims and Hypotheses

      The study addressed 2 aims: (1) characterize practice patterns surrounding the diagnosis and management of IBS and (2) explore resource use, comorbidities, and medical interventions in patients with IBS compared with patients without IBS in general medical practice.
      We hypothesized that (1) most IBS diagnoses occur in the primary care setting; (2) many IBS diagnoses are made without extensive use of medical tests; (3) patients with IBS undergo more laboratory tests, endoscopies, and surgical interventions than patients without IBS; (4) patients with IBS suffer from psychiatric comorbidities and chronic pain conditions at higher rates than patients without IBS; (5) patients diagnosed initially with IBS are rarely diagnosed later with a different gastrointestinal disorder that could explain their symptoms; (6) patients with IBS are treated with psychiatric medications at higher rates than patients without IBS; and (7) patients diagnosed with IBS by gastroenterologists undergo more intensive testing and treatment and suffer more comorbidities than patients diagnosed by nongastroenterologists.

       Source of Study Population and Clinical Setting

      From 1995–2005, 2.4–3.2 million people (51% female, 75% adult) were enrolled in KPNC. This member population is demographically representative of the general population of northern California. Physicians from the Permanente Medical Group, Inc provide nearly all care to Kaiser Permanente members in northern California. Before 2006, physicians entered diagnoses on scannable sheets at the end of a visit. Since 2006, they have entered diagnoses into the electronic medical record.
      In 2011, there were approximately 1400 clinicians (96% physicians and the rest nurse practitioners and physician assistants), including approximately 120 gastroenterologists, providing adult medicine care in KPNC. KPNC does not have guidelines for IBS testing or management.

       Data Sources

      The KPNC databases that were searched consisted of those recording outpatient visits and diagnoses, outpatient procedures, inpatient visits and diagnoses, inpatient procedures, laboratory tests, medications, and radiology studies. Data sets for the identified IBS patients and controls were merged for final analysis.

       Identification of Irritable Bowel Syndrome Patients and Controls

      Databases recording outpatient and inpatient diagnoses were searched to identify all patients who received a diagnosis of IBS on at least 1 encounter from 1995–2005. The 3 KPNC labels linked to International Classification of Diseases, ninth revision code 564.1 for IBS are “Irritable bowel syn.,” “Irritable bowel syndrome,” and “Irritable bowel syndrome (IBS).” Demographic characteristics for these IBS patients were then determined, including gender, age, and period of coverage by KPNC.
      The same databases were then searched to identify controls, defined as patients who never received a diagnosis of IBS. Controls were matched to subjects by gender, date of birth, first year of KPNC membership, last year of KPNC membership, and number of years of KPNC membership. For dates and time periods, matching was performed within 1 year, and if no match was found for all parameters, then within 2 years.
      Matching for length of coverage was performed to have comparable periods of observation in both groups in which diagnoses could have been made, tests undertaken, medications prescribed, and interventions performed. Matching for calendar period of coverage was performed to minimize differences between patients that could be attributed to secular trends in practice patterns or resource use. Follow-up was available through 2007.

       Variables Studied

       Demographics and factors related to the diagnosis of irritable bowel syndrome

      We summarized demographic characteristics for IBS patients and controls and compared race and ethnicity, because no matching was performed for these variables. We determined the period of coverage before and after IBS diagnosis, ascertained what fraction of IBS diagnoses were made in the primary versus the secondary care setting, and determined the rates of lower endoscopy and whether endoscopy preceded the diagnosis of IBS.

       Medical tests

      We determined the proportions of patients who underwent the following tests at least once:
      • 1
        Laboratory tests: complete blood count, sedimentation rate, electrolytes and renal chemistries (blood urea nitrogen and creatinine), liver chemistries (alanine and aspartate aminotransferases, alkaline phosphatase, bilirubin), thyroid function tests (thyroid-stimulating hormone and thyroxine levels), celiac disease antibodies (antigliadin and tissue transglutaminase), and Helicobacter pylori antibodies.
      • 2
        Stool tests: fecal leukocytes, fecal occult blood testing, fecal fat.
      • 3
        Endoscopic tests: sigmoidoscopy, colonoscopy, upper endoscopy, endoscopic retrograde cholangiopancreatography.
      • 4
        Radiologic tests: abdominal film, barium enema, abdominal sonogram, computed tomography of the abdomen and/or pelvis, magnetic resonance imaging of the abdomen and/or pelvis, upper gastrointestinal series, small bowel follow-through study.
      For sigmoidoscopy and colonoscopy, we ascertained the timing of the test with respect to the first diagnosis of IBS to clarify whether the test might have been performed as part of the prediagnosis evaluation, reasoning that tests performed after a diagnosis of IBS was coded could not have been part of the prediagnosis investigation. We did not find adequately coded information to determine rates of stool testing for parasites.

       Comorbidities and other gastrointestinal diagnoses

      We determined the proportions of IBS patients and controls who received the following diagnoses at least once, including the multiple possible KPNC labels for each International Classification of Diseases, ninth revision code associated with each diagnosis:
      • 1
        Psychiatric: anxiety, depression, bipolar affective disorder, psychosis.
      • 2
        Somatic pain: migraine, fibromyalgia, chronic pain syndrome.
      • 3
        Metabolic: diabetes.
      • 4
        Gastrointestinal: celiac disease, colitis, Crohn's disease, inflammatory bowel disease, colorectal cancer.

       Medication use

      We determined the proportions of patients who were prescribed the following medications at least once:
      • 1
        Antidiarrheals: loperamide, diphenoxylate/atropine.
      • 2
        IBS medications: alosetron, tegaserod.
      • 3
        Antispasmodics: dicyclomine, hyoscyamine.
      • 4
        Anxiolytics: benzodiazepines.
      • 5
        Antidepressants: tricyclic antidepressant (TCA), selective serotonin reuptake inhibitor (SSRI), other antidepressant.
      We attempted to determine the rates of use of fiber and laxatives but did not find adequately coded information in the databases.

       Surgical interventions

      We determined the proportions of patients who underwent the following types of surgical interventions at least once: esophageal, gastric, intestinal, rectal, biliary, gynecologic.

       Patients diagnosed by gastroenterologists versus nongastroenterologists

      We contrasted diagnostic and management practices among patients diagnosed with IBS by gastroenterologists versus nongastroenterologists.

       Statistical Analysis

      Analyses were performed with SAS 9.1 software (SAS Institute Inc, Cary, NC). Summary statistics were calculated. Data from IBS patients and controls and from patients diagnosed by gastroenterologists and nongastroenterologists were compared with t tests or χ2 tests, and odds ratios (ORs) were calculated with 95% confidence intervals (CIs). Predictors of test utilization and treatment, including demographic information and diagnosis by gastroenterologists or nongastroenterologists, were analyzed by multivariate logistic regression analysis.

      Results

       Study Patients

      From 1995–2005, IBS was diagnosed in 141,295 individuals. The mean age at diagnosis was 46 years, standard deviation (SD) 17.0 years, and the majority were women (Table 1). There were more white and Hispanic or Latino persons among IBS patients than controls, but race and ethnicity was more often coded as unknown in controls than in IBS patients, limiting the ability to reach conclusions about different distributions of race and ethnicity between groups (Table 1). The mean time of enrollment in KPNC before IBS diagnosis was 4.1 years, SD 3.2 years, and the mean time of enrollment after IBS diagnosis was 4.7 years, SD 3.3 years.
      Table 1Demographic Characteristics of Study Subjects
      IBS n = 141,295Control n = 141,294IBS vs control (P value)IBS diagnosed by GI
      Provider specialty known for 83% of IBS patients.
      n = 14,640
      IBS diagnosed by non-GI
      Provider specialty known for 83% of IBS patients.
      n = 102,187
      IBS diagnosed by GI vs non-GI (P value)
      Mean age (SD) in 2007, y53.0 (17.4)53.0 (17.4)NA55.9 (16.0)53.0 (17.5)NA
      Gender
       Women104,047 (73.6%)104,037 (73.6%)NA11,184 (76.4%)74,552 (73.0%)NA
       Men37,237 (26.4%)37,247 (26.4%)NA3455 (23.6%)27,626 (27.0%)NA
      Race and ethnicity
       White74,635 (52.8%)60,882 (43.1%)<.00018592 (58.7%)53,383 (52.2%)<.0001
       Black7861 (5.6%)8405 (5.9%)1140 (7.8%)5526 (5.4%)
       Asian8896 (6.3%)12,471 (8.8%)857 (5.9%)6730 (6.6%)
       Hispanic or Latino11,668 (8.3%)9904 (7.0%)1159 (7.9%)8542 (8.4%)
       Native American732 (0.5%)557 (0.4%)99 (0.7%)507 (0.5%)
       Mixed4973 (3.5%)3927 (2.8%)586 (4.0%)3532 (3.5%)
       Other533 (0.4%)660 (0.5%)61 (0.4%)398 (0.4%)
       Unknown31,997 (22.6%)44,488 (31.5%)2146 (14.7%)23,569 (23.1%)
      Mean coverage period (SD), y8.0 (3.4)8.0 (3.4)NA8.5 (3.2)8.0 (3.4)NA
      Mean coverage period before IBS diagnosis coded (SD), y4.1 (3.2)NA4.5 (3.1)4.4 (3.2)
      Mean coverage period after IBS diagnosis coded (SD), y4.7 (3.3)NA4.7 (3.2)4.4 (3.1)
      GI, gastroenterologist; NA, not applicable.
      a Provider specialty known for 83% of IBS patients.

       Point of Diagnosis and Use of Endoscopy

      Among the 83% of patients for whom provider specialty was known, nongastroenterologist internists made 68% of IBS diagnoses, gastroenterologists 13%, and other physicians 19%. Among nongastroenterologist internists, 87% of IBS diagnoses were made by general internists, 6% by hospitalists, 1% each by endocrinologists and rheumatologists, and the remainder by other subspecialists. Among other physicians, 68% of IBS diagnoses were made by family practitioners, 2% by pediatricians, <1% each by surgeons, gynecologists, and psychiatrists, and the remainder by other specialists.
      In the majority of cases, an IBS diagnosis was coded without a preceding lower endoscopic procedure. The IBS diagnosis was preceded by sigmoidoscopy in 29,159 patients (20.6% of IBS patients, 5.1 sigmoidoscopies/100 person-years, accounting for 49.6% of sigmoidoscopies in IBS patients) and by colonoscopy in 7,497 patients (5.3% of IBS patients, 1.3 colonoscopies/100 person-years, accounting for 37.4% of colonoscopies in IBS patients).

       Blood and Stool Tests

      IBS patients were significantly more likely than controls to undergo common laboratory blood tests (Table 2). A small minority of IBS patients underwent stool testing for white cells, blood, or fat, but the proportion was higher than among controls (Table 2). Testing for celiac disease was rare among IBS patients (2.7%) but more common than among controls (OR, 10.7; 95% CI, 9.62–11.9). All of the celiac disease tests in patients with IBS occurred after 2001.
      Table 2Laboratory and Stool Tests in IBS Patients Versus Controls
      IBSControlIBS vs control, OR (95% CI)P valueIBS diagnosed by GI
      Provider specialty known for 83% of IBS patients.
      IBS diagnosed by non-GI
      Provider specialty known for 83% of IBS patients.
      IBS diagnosed by GI vs non-GI, OR (95% CI)P value
      Blood tests
       Any complete blood count134,688 (95.3%)116,065 (82.1%)4.43 (4.31–4.56)<.000114,438 (98.6%)97,468 (95.4%)3.46 (3.00–3.99)<.0001
       Any sedimentation rate67,961 (48.1%)37,700 (26.7%)2.55 (2.51–2.59)<.00018992 (61.4%)48,216 (47.2%)1.78 (1.72–1.85)<.0001
       Any renal chemistry panel124,901 (88.4%)102,687 (72.7%)2.86 (2.81–2.92)<.000113,883 (94.8%)90,838 (88.9%)2.29 (2.12–2.47)<.0001
       Any glucose129,328 (91.5%)109,556 (77.5%)3.13 (3.06–3.20)<.000114,022 (95.8%)93,964 (92.0%)1.99 (1.83–2.16)<.0001
       Any liver function tests123,200 (87.2%)94,276 (66.7%)3.40 (3.33–3.46)<.000113,799 (94.3%)89,589 (87.7%)2.31 (2.15–2.48)<.0001
       Any thyroid function tests124,292 (88.0%)101,011 (71.5%)2.92 (2.86–2.97)<.000113,642 (93.2%)90,417 (88.5%)1.78 (1.66–1.90)<.0001
       Any celiac disease tests3825 (2.7%)366 (0.3%)10.71 (9.62–11.93)<.0001758 (5.2%)2713 (2.7%)2.00 (1.84–2.17)<.0001
       Any H pylori serology test1487 (1.1%)371 (0.3%)4.04 (3.60–4.53)<.0001257 (1.8%)841 (0.8%)2.15 (1.87–2.48)<.0001
      Stool tests
       Any stool white cells test6933 (4.9%)1995 (1.4%)3.60 (3.43–3.79)<.00011009 (6.9%)4690 (4.6%)1.54 (1.43–1.65)<.0001
       Any fecal occult blood test29,517 (20.9%)18,148 (12.8%)1.79 (1.76–1.83)<.00013869 (26.4%)21,472 (21.0%)1.35 (1.30–1.40)<.0001
       Any fecal fat test2369 (1.7%)265 (0.2%)9.07 (7.99–10.31)<.0001534 (3.6%)1504 (1.5%)2.53 (2.29–2.80)<.0001
      Endoscopic tests
       Sigmoidoscopy58,788 (41.6%)31,411 (22.2%)2.49 (2.45–2.53)<.00018795 (60.1%)41,607 (40.7%)2.19 (2.11–2.27)<.0001
       Colonoscopy20,069 (14.2%)8746 (6.2%)2.51 (2.44–2.58)<.00014421 (30.2%)13,134 (12.9%)2.93 (2.82–3.05)<.0001
       Upper endoscopy19,942 (14.1%)6592 (4.7%)3.36 (3.26–3.46)<.00014635 (31.7%)12,760 (12.5%)3.25 (3.12–3.38)<.0001
       Endoscopic retrograde cholangiopancreatography784 (0.6%)326 (0.2%)2.41 (2.12–2.75)<.0001183 (1.3%)493 (0.5%)2.61 (2.20–3.10)<.0001
      Radiologic tests
       Abdominal x-ray30,249 (21.4%)12,791 (9.1%)2.74 (2.68–2.80)<.00014596 (31.4%)21,327 (20.9%)1.73 (1.67–1.80)<.0001
       Barium enema23,960 (17.0%)5767 (4.1%)4.80 (4.66–4.94)<.00013625 (24.8%)17,663 (17.3%)1.57 (1.51–1.64)<.0001
       Computed tomography, pelvis27,900 (19.7%)12,666 (9.0%)2.50 (2.44–2.56)<.00014659 (31.8%)19,870 (19.4%)1.93 (1.86–2.01)<.0001
       Computed tomography, abdomen32,206 (22.8%)14,671 (10.4%)2.55 (2.49–2.60)<.00015397 (36.9%)22,871 (22.4%)2.02 (1.95–2.10)<.0001
       Magnetic resonance imaging, pelvis699 (0.5%)449 (0.3%)1.56 (1.38–1.76)<.0001102 (0.7%)497 (0.5%)1.44 (1.16–1.78).0009
       Magnetic resonance imaging, abdomen675 (0.5%)317 (0.2%)2.13 (1.87–2.44)<.0001127 (0.9%)476 (0.5%)1.87 (1.54–2.28)<.0001
       Ultrasound, pelvis36,797 (26.0%)21,194 (15.0%)2.00 (1.96–2.03)<.00014824 (33.0%)26,454 (25.9%)1.41 (1.36–1.46)<.0001
       Ultrasound, abdomen49,857 (35.3%)22,440 (15.9%)2.89 (2.84–2.94)<.00017477 (51.1%)35,461 (34.7%)1.96 (1.90–2.03)<.0001
       Upper gastrointestinal series18,734 (13.3%)5334 (3.8%)3.90 (3.78–4.02)<.00013232 (22.1%)13,166 (12.9%)1.92 (1.83–2.00)<.0001
       Small bowel follow-through5903 (4.2%)1065 (0.8%)5.74 (5.38–6.13)<.00011503 (10.3%)3650 (3.6%)3.09 (2.90–3.29)<.0001
      GI, gastroenterologist; NA, not applicable.
      a Provider specialty known for 83% of IBS patients.

       Endoscopic and Radiologic Tests

      IBS patients were significantly more likely than controls to undergo endoscopic testing including sigmoidoscopy, colonoscopy, upper endoscopy, and endoscopic retrograde cholangiopancreatography, as well as all categories of abdominal and pelvic imaging (Table 2).

       Comorbidities and Other Gastrointestinal Diagnoses

      IBS patients were significantly more likely than controls to be diagnosed with chronic pain syndrome and psychiatric comorbidities (Table 3). Very few IBS patients went on to receive other gastrointestinal diagnoses that potentially could explain abdominal pain and altered defecation (Table 3). The mean time until another gastrointestinal diagnosis was made was 1.7 years (SD, 1.8) for inflammatory bowel disease, 2.5 years (SD, 2.8) for colitis, 2.4 years (SD, 2.6) for Crohn's disease, and 2.8 years (SD, 3) for celiac disease. The prevalence of diabetes was slightly lower in IBS patients than in controls (9.6% vs 10.4%; OR, 0.91; 95% CI, 0.89–0.93).
      Table 3Comorbidities in IBS Patients Versus Controls
      IBSControlIBS vs control, OR (95% CI)P valueIBS diagnosed by GI
      Provider specialty known for 83% of IBS patients.
      IBS diagnosed by non-GI
      Provider specialty known for 83% of IBS patients.
      IBS diagnosed by GI vs non-GI, OR (95% CI)P value
      Other pain syndromes
       Migraine51,886 (36.7%)28,380 (20.1%)2.31 (2.27–2.35)<.00016108 (41.7%)37,534 (36.7%)1.23 (1.19–1.28)<.0001
       Fibromyalgia8288 (5.9%)1900 (1.3%)4.57 (4.35–4.81)<.00011179 (8.1%)6070 (5.9%)1.39 (1.30–1.48)<.0001
       Chronic pain26,467 (18.7%)10,568 (7.5%)2.85 (2.78–2.92)<.00013781 (25.8%)19,217 (18.8%)1.50 (1.44–1.56)<.0001
      Psychiatric comorbidities
       Anxiety51,452 (36.4%)21,724 (15.4%)3.15 (3.10–3.21)<.00015745 (39.2%)37,773 (37.0%)1.10 (1.06–1.14)<.0001
       Depression55,117 (39.0%)27,507 (19.5%)2.65 (2.60–2.69)<.00016308 (43.1%)39,994 (39.1%)1.18 (1.14–1.22)<.0001
       Bipolar4585 (3.2%)1894 (1.3%)2.47 (2.34–2.61)<.0001594 (4.1%)3261 (3.2%)1.28 (1.17–1.40)<.0001
       Psychosis662 (0.5%)379 (0.3%)1.75 (1.54–1.99)<.0001106 (0.7%)463 (0.5%)1.60 (1.30–1.98)<.0001
      Other medical diagnoses
       Diabetes13,558 (9.6%)14,730 (10.4%)0.91 (0.89–0.93)<.00011759 (12.0%)9643 (9.4%)1.31 (1.24–1.38)<.0001
       Celiac disease136 (0.1%)26 (0.0%)5.23 (3.44–7.96)<.000128 (0.2%)100 (0.1%)1.96 (1.29–2.98).0014
       Crohn's disease954 (0.7%)221 (0.2%)4.34 (3.75–5.02)<.0001313 (2.1%)499 (0.5%)4.45 (3.86–5.13)<.0001
       Colitis2723 (1.9%)774 (0.5%)3.57 (3.29–3.87)<.0001685 (4.7%)1577 (1.5%)3.13 (2.86–3.43)<.0001
       Inflammatory bowel disease1560 (1.1%)246 (0.2%)6.40 (5.59–7.32)<.0001373 (2.5%)937 (0.9%)2.83 (2.50–3.19)<.0001
      GI, gastroenterologist; NA, not applicable.
      a Provider specialty known for 83% of IBS patients.

       Medication Use

      IBS patients were often prescribed antidiarrheal and antispasmodic medications (Table 4). IBS patients were significantly more likely than controls to be prescribed anxiolytics and antidepressants (Table 4), with 38% of prescriptions for psychotropics made after and 62% before IBS diagnosis. Nearly half of all IBS patients were treated at one point with an anxiolytic, and more than half of all IBS patients were treated at one point with an antidepressant, with TCAs and SSRIs each used in approximately one-third of IBS patients (Table 4).
      Table 4Medications Prescribed to IBS Patients Versus Controls
      IBSControlIBS vs control, OR (95% CI)P valueIBS diagnosed by GI
      Provider specialty known for 83% of IBS patients.
      IBS diagnosed by non-GI
      Provider specialty known for 83% of IBS patients.
      IBS diagnosed by GI vs non-GI, OR (95% CI)P value
      IBS prescriptions
       Antispasmodics80,205 (56.8%)13,112 (9.3%)12.83 (12.57–13.10)<.00019032 (61.7%)58,106 (56.9%)1.22 (1.18–1.27)<.0001
       Prescription antidiarrheal21,573 (15.3%)6767 (4.8%)3.58 (3.48–3.69)<.00013163 (21.6%)15,080 (14.8%)1.59 (1.52–1.66)<.0001
       Prescription laxative4122 (2.9%)2736 (1.9%)1.52 (1.45–1.60)<.0001698 (4.8%)2733 (2.7%)1.82 (1.67–1.98)<.0001
       Prescription fiber125 (0.1%)94 (0.1%)1.33 (1.02–1.74).036114 (0.1%)87 (0.1%)1.12 (0.64–1.98).6863
       Alosetron133 (0.1%)2 (0.0%)66.56 (16.47–268.9)<.000134 (0.2%)92 (0.1%)2.58 (1.74–3.83)<.0001
       Tegaserod748 (0.5%)21 (0.0%)35.80 (23.20–55.24)<.0001178 (1.2%)508 (0.5%)2.46 (2.08–2.92)<.0001
      Psychiatric medications
       Anxiolytics62,844 (44.5%)37,863 (26.8%)2.19 (2.15–2.22)<.00017927 (54.1%)44,991 (44.0%)1.50 (1.45–1.55)<.0001
       Any antidepressant77,563 (54.9%)41,446 (29.3%)2.93 (2.89–2.98)<.00019477 (64.7%)56,005 (54.8%)1.51 (1.46–1.57)<.0001
       TCA46,656 (33.0%)19,551 (13.8%)3.07 (3.01–3.13)<.00016473 (44.2%)33,312 (32.6%)1.64 (1.58–1.70)<.0001
       SSRI50,714 (35.9%)25,050 (17.7%)2.60 (2.55–2.64)<.00016028 (41.2%)36,741 (36.0%)1.25 (1.20–1.29)<.0001
       Other antidepressant37,439 (26.5%)18,371 (13.0%)2.41 (2.37–2.46)<.00014913 (33.6%)26,914 (26.3%)1.41 (1.36–1.47)<.0001
      GI, gastroenterologist; NA, not applicable.
      a Provider specialty known for 83% of IBS patients.
      Among IBS patients treated with anxiolytics, 45% did not have a diagnosis of anxiety, 30% received anxiolytics before a diagnosis of anxiety, and 25% received them after a diagnosis of anxiety. Among controls treated with anxiolytics, the respective fractions were 66%, 18%, and 16%.
      Among IBS patients treated with antidepressants, 37% did not have a diagnosis of depression, 34% received antidepressants before a diagnosis of depression, and 29% received them after a diagnosis of depression. Among controls treated with antidepressants, the respective fractions were 45%, 26%, and 29%.

       Surgical Interventions

      The rate of abdominal and pelvic surgery during the study period was low in both groups, but IBS patients were more likely than controls to undergo an operation in all of the categories assessed (Table 5).
      Table 5Operations in IBS Patients Versus Controls
      IBSControlIBS vs control, OR (95% CI)P valueIBS diagnosed by GI
      Provider specialty known for 83% of IBS patients.
      IBS diagnosed by non-GI
      Provider specialty known for 83% of IBS patients.
      IBS diagnosed by GI vs non-GI, OR (95% CI)P value
      Esophageal221 (0.2%)172 (0.1%)1.29 (1.05–1.57).013452 (0.4%)130 (0.1%)2.80 (2.03–3.86)<.0001
      Gastric1262 (0.9%)734 (0.5%)1.73 (1.58–1.89)<.0001257 (1.8%)809 (0.8%)2.24 (1.94–2.58)<.0001
      Rectal1936 (1.4%)1083 (0.8%)1.80 (1.67–1.94)<.0001286 (2.0%)1354 (1.3%)1.48 (1.30–1.69)<.0001
      Intestinal6921 (4.9%)3864 (2.7%)1.83 (1.76–1.91)<.00011134 (7.7%)4734 (4.6%)1.73 (1.62–1.85)<.0001
      Abdominal3147 (2.2%)1376 (1.0%)2.32 (2.17–2.47)<.0001505 (3.4%)2057 (2.0%)1.74 (1.58–1.92)<.0001
      Biliary8266 (5.9%)4094 (2.9%)2.08 (2.00–2.16)<.00011190 (8.1%)5825 (5.7%)1.46 (1.37–1.56)<.0001
      Gynecologic12,154 (8.6%)8489 (6.0%)1.47 (1.43–1.52)<.00011547 (10.6%)8543 (8.4%)1.30 (1.22–1.37)<.0001
      GI, gastroenterologist; NA, not applicable.
      a Provider specialty known for 83% of IBS patients.

       Patients Diagnosed by Gastroenterologists Versus Nongastroenterologists

      Patients diagnosed with IBS by gastroenterologists demonstrated patterns of more intensive testing, greater comorbidity, and more intensive treatment than patients diagnosed by nongastroenterologists (Table 2, Table 3, Table 4, Table 5).

       Predictors of Testing and Treatment

      In multivariate logistic regression models, having IBS diagnosed by a gastroenterologist had the strongest association with endoscopic and radiologic testing. For example, in a model with white as the reference race/ethnicity, the adjusted ORs for undergoing a colonoscopy were 1.035 (95% CI, 1.033–1.036) per 1-year increase in age, 0.82 (95% CI, 0.79–0.86) for women versus men, 0.79 (95% CI, 0.73–0.85) for blacks, 0.81 (95% CI, 0.76–0.86) for Hispanics/Latinos, 0.79 (95% CI, 0.74–0.85) for Asian Americans, 1.20 (95% CI, 0.98–1.48) for Native Americans, and 2.82 (95% CI 2.71–2.94) for having IBS diagnosis by a gastroenterologist versus nongastroenterologist. The ORs for undergoing any sigmoidoscopy were of similar magnitude as those for colonoscopy, but non-whites were more likely to undergo sigmoidoscopy than whites. Overall, the strengths of the associations with radiologic testing were similar to those with endoscopic testing, but women were more likely than men to undergo pelvic imaging.
      In contrast, sex was the variable with the strongest association with psychotropic medication use. For example, the adjusted ORs for receiving an antidepressant prescription were 1.014 (95% CI, 1.013–1.015) per 1-year increase in age, 1.86 (95% CI, 1.81–1.91) for women versus men, 0.77 (95% CI, 0.74–0.82) for blacks, 0.81 (95% CI, 0.78–0.86) for Hispanics/Latinos, 0.40 (95% CI, 0.38–0.42) for Asian Americans, 1.10 (95% CI, 0.93–1.31) for Native Americans, and 1.36 (95% CI, 1.31–1.41) for having IBS diagnosis by a gastroenterologist versus nongastroenterologist. The results for anxiolytics were very similar to those for antidepressants, except that blacks were more likely than whites to receive an anxiolytic prescription (OR, 1.08; 95% CI, 1.02–1.13).

      Discussion

      In this large observational study, we investigated practice patterns associated with the diagnosis and management of IBS and comorbidities associated with IBS in members of a large health maintenance organization. Although our observations might not be generalizable to all practice settings, they provide insight into the point of diagnosis, testing, management, and comorbidities of IBS patients across the spectrum of care in general medical practice, with medium-term follow-up.
      In our cohort, the majority of IBS diagnoses were made in the primary care setting and usually without preceding lower endoscopy. Having IBS diagnosed by a gastroenterologist was the variable with the strongest association with endoscopic and radiologic testing. This is notable in light of prior studies suggesting that primary care physicians might be more likely than gastroenterologists to view IBS as a diagnosis of exclusion.
      • Spiegel B.
      • Farid M.
      • Esrailian E.
      • et al.
      Is irritable bowel syndrome a diagnosis of exclusion? A survey of primary care providers, gastroenterologists, and IBS experts.
      Although we could not ascertain what the indications were for tests or interventions, IBS patients were more likely than controls to undergo all of the common blood, stool, endoscopic, and radiologic tests and all of the types of abdominal and pelvic operations that we studied. These findings are consistent with several prior studies that report increased health care resource use among patients with IBS.
      • Longstreth G.F.
      • Yao J.F.
      Irritable bowel syndrome and surgery: a multivariable analysis.
      • Lu C.L.
      • Liu C.C.
      • Fuh J.L.
      • et al.
      Irritable bowel syndrome and negative appendectomy: a prospective multivariable investigation.
      • Johannson A.
      • Farup G.
      • Bracco A.
      • et al.
      How does comorbidity affect cost of health care in patients with irritable bowel syndrome? A cohort study in general practice.
      • Spiegel B.
      • Kanwal F.
      • Naliboff B.
      • et al.
      The impact of somatization on the use of gastrointestinal health-care resources in patients with irritable bowel syndrome.
      • Talley N.J.
      Unnecessary abdominal and back surgery in irritable bowel syndrome: time to stem the flood now?.
      Most of these previous studies did not examine the specific types of tests or interventions in detail. Our study provides a detailed accounting during a reasonably long period of follow-up.
      Although celiac disease testing was performed more frequently in patients diagnosed with IBS than in controls, it was still uncommon in the IBS group and occurred only after 2001, when the presence of celiac disease among a minority of IBS patients became well-recognized. Admittedly, recommendations that patients with suspected IBS be tested for celiac disease are relatively recent.
      • Spiller R.
      • Aziz Q.
      • Creed F.
      • et al.
      Guidelines on the irritable bowel syndrome: mechanisms and practical management.
      • Brandt L.J.
      • Chey W.D.
      • Foxx-Orenstein A.E.
      • et al.
      An evidence-based position statement on the management of irritable bowel syndrome.
      The proportion of patients with IBS in our cohort who went on to receive other gastrointestinal diagnoses that could potentially explain their symptoms was very low, which is consistent with reports by other investigators.
      As has been observed previously, patients with IBS in our cohort had higher comorbidities of somatic pain syndromes including fibromyalgia, migraine, and chronic pain and psychiatric comorbidity than controls, including high rates of anxiety and depression. The rates of psychiatric comorbidity in IBS vary widely in the literature, ranging from 18% of IBS patients in the community to up to 94% of those referred to speciality centers.
      • Walker E.A.
      • Katon W.J.
      • Jemelka R.P.
      • et al.
      Comorbidity of gastrointestinal complaints, depression, and anxiety in the Epidemiologic Catchment Area (ECA) Study.
      The rates of anxiety and depression observed in this study are consistent with previously reported data on IBS patients presenting to outpatient clinics.
      • Thijssen A.Y.
      • Jonkers D.M.
      • Leue C.
      • et al.
      Dysfunctional cognitions, anxiety and depression in irritable bowel syndrome.
      • Drossman D.A.
      • Camilleri M.
      • Mayer E.A.
      • et al.
      AGA technical review on irritable bowel syndrome.
      Fibromyalgia has been reported previously in more than 30% of patients with IBS,
      • Whitehead W.E.
      • Palsson O.
      • Jones K.R.
      Systematic review of the comorbidity of irritable bowel syndrome with other disorders: what are the causes and implications?.
      • Vandvik P.O.
      • Lydersen S.
      • Farup P.G.
      Prevalence, comorbidity and impact of irritable bowel syndrome in Norway.
      in contrast with the 5.9% observed in our cohort. This might reflect differences in study populations, because our cohort reflects the general membership of a large health maintenance organization and not selected patients in referral settings, but it might also reflect under-recognition of fibromyalgia in clinical practice in the absence of an active effort to ascertain its prevalence. The prevalence of migraine of 36.7% in our IBS cohort was significantly higher than the rate of 6% previously reported in a large IBS cohort,
      • Cole J.
      • Rothman K.
      • Cabral H.
      • et al.
      Fibromyalgia and depression among people with IBS: a prevalence study.
      and it is more consistent with the prevalence of “headache” reported in IBS patients.
      • Zaman M.
      • Chavez N.
      • Krueger R.
      • et al.
      Extra-intestinal symptoms in patients with irritable bowel syndrome (IBS).
      • Jones K.
      • Palsson O.
      • Levy R.
      • et al.
      Comorbid disorders and symptoms in irritable bowel syndrome (IBS) compared to other gastroenterology patients.
      • Maxton D.G.
      • Morris J.
      • Whorwell P.J.
      More accurate diagnosis of irritable bowel syndrome by the use of “non-colonic” symptomatology.
      As would be expected, IBS patients commonly received prescriptions for antispasmodic and antidiarrheal medication. It is likely that the use of antidiarrheal medication, laxatives, and fiber was substantially higher than was recorded in the databases, because over-the-counter use was not captured. The use of anxiolytic and antidepressant medications was substantial in both IBS patients and controls, but significantly higher in IBS patients. Sex was the variable with the strongest association with psychotropic medication use, with women being more likely than men to receive these medications. Of note, the majority of antidepressants were prescribed before IBS diagnosis, possibly reflecting the high prevalence of depression and other chronic pain syndromes in patients with IBS.
      The strengths of this study include its large size and the inclusion of controls matched for age, gender, and length of enrollment in KPNC. The time period of observation before and after IBS diagnosis is reasonably long. The study provides novel data on the proportion of IBS diagnoses made in the primary care setting, the rates of lower endoscopy and whether endoscopy preceded the IBS diagnosis, and the percentage of psychotropic medications prescribed before versus after IBS diagnosis. Although other studies have emphasized the importance of screening for celiac disease in patients with IBS,
      • Ford A.C.
      • Chey W.D.
      • Talley N.J.
      • et al.
      Yield of diagnostic tests for celiac disease in individuals with symptoms suggestive of irritable bowel syndrome: systematic review and meta-analysis.
      • Jadallah K.A.
      • Khader Y.S.
      Celiac disease in patients with presumed irritable bowel syndrome: a case-finding study.
      • Zwolińska-Wcisło M.
      • Galicka-Latała D.
      • Rozpondek P.
      • et al.
      [Frequency of celiac disease and irritable bowel syndrome coexistance and its influence on the disease course].
      • Cash B.D.
      • Schoenfeld P.
      • Chey W.D.
      The utility of diagnostic tests in irritable bowel syndrome patients: a systematic review.
      • Korkut E.
      • Bektas M.
      • Oztas E.
      • et al.
      The prevalence of celiac disease in patients fulfilling Rome III criteria for irritable bowel syndrome.
      we are not aware of other large studies reporting the frequency with which practitioners have actually screened for celiac disease in an IBS population or the proportion of IBS patients eventually diagnosed as having celiac disease. Finally, it has been suggested that diabetes might exacerbate IBS symptoms,
      • Kim J.H.
      • Park H.S.
      • Ko S.Y.
      • et al.
      Diabetic factors associated with gastrointestinal symptoms in patients with type 2 diabetes.
      • Koch C.A.
      • Uwaifo G.I.
      Are gastrointestinal symptoms related to diabetes mellitus and glycemic control?.
      but the comparable prevalence of diabetes in IBS patients and controls in our study suggests that IBS-type symptoms were unlikely to be explained by diabetes in most cases.
      Our study has limitations. First, the results might not be generalizable to practice settings that are different from KPNC. Although KPNC does not have guidelines for the management of IBS, it is possible that patterns of specialty encounters and testing differ between KPNC and other settings. Although the KPNC population is demographically representative of the general population of northern California, it might not be representative of the United States as a whole, and it is an insured population that could differ from noninsured populations. Second, the study was retrospective and relied on queries of multiple databases. There was no standardized set of clinical criteria for arriving at a diagnosis of IBS. Rather, the results reflect the concept of IBS as used in clinical practice. IBS diagnoses were not confirmed by chart review or patient questionnaire. Third, the symptoms associated with the diagnosis for IBS patients in this study could not be ascertained. Thus, although IBS patients underwent more testing than their non-IBS counterparts, it is unclear how many IBS patients had “alarm symptoms” such as weight loss or rectal bleeding that might have warranted further testing even if patients met clinical criteria for IBS. Fourth, we did not assess all comorbidities that have been reported to occur more frequently in IBS patients, including chronic fatigue,
      • Jones K.
      • Palsson O.
      • Levy R.
      • et al.
      Comorbid disorders and symptoms in irritable bowel syndrome (IBS) compared to other gastroenterology patients.
      functional dyspepsia,
      • Ford A.C.
      • Marwaha A.
      • Lim A.
      • et al.
      Systematic review and meta-analysis of the prevalence of irritable bowel syndrome in individuals with dyspepsia.
      • Caballero-Plasencia A.M.
      • Sofos-Kontoyannis S.
      • Valenzuela-Barranco M.
      • et al.
      Irritable bowel syndrome in patients with dyspepsia: a community-based study in southern Europe.
      • Wang A.
      • Liao X.
      • Xiong L.
      The clinical overlap between functional dyspepsia and irritable bowel syndrome based on Rome III criteria.
      • Agréus L.
      • Svarsudd K.
      • Nyrén O.
      • et al.
      Irritable bowel syndrome and dyspepsia in the general population: overlap and lack of stability over time.
      somatization disorder,
      • Miller A.R.
      • North C.S.
      • Clouse R.E.
      • et al.
      The association of irritable bowel syndrome and somatization disorder.
      • North C.S.
      • Downs D.
      • Clouse R.E.
      • et al.
      The presentation of irritable bowel syndrome in the context of somatization disorder.
      • Lydiard R.B.
      • Fossey M.D.
      • Marsh W.
      • et al.
      Prevalence of psychiatric disorders in patients with irritable bowel syndrome.
      • Koloski N.A.
      • Boyce P.M.
      • Talley N.J.
      Somatization an independent psychosocial risk factor for irritable bowel syndrome but not dyspepsia: a population-based study.
      temporomandibular joint pain,
      • Jones K.
      • Palsson O.
      • Levy R.
      • et al.
      Comorbid disorders and symptoms in irritable bowel syndrome (IBS) compared to other gastroenterology patients.
      • Aaron L.
      • Burke M.
      • Buchwald D.
      Overlapping conditions among patients with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder.
      and dyspareunia.
      • Whitehead W.E.
      • Palsson O.
      • Jones K.R.
      Systematic review of the comorbidity of irritable bowel syndrome with other disorders: what are the causes and implications?.
      We did not explore in detail the overlap between IBS and pelvic pain, including visits to gynecologists.
      • Choung R.S.
      • Herrick L.M.
      • Locke 3rd, G.R.
      • et al.
      Irritable bowel syndrome and chronic pelvic pain: a population-based study.
      • Walker E.A.
      • Gelfand A.N.
      • Gelfand M.D.
      • et al.
      Chronic pelvic pain and gynecological symptoms in women with irritable bowel syndrome.
      Although we observed high rates of diagnoses of anxiety and depression, we were not able to elucidate more specifically the types of anxiety or depression observed in IBS patients (ie, generalized anxiety disorder, panic, single episode vs recurrent major depression, dysthmyia, etc). Further delineation of the type of anxiety or depression, as well as ascertainment of the prevalence of personality disorders in IBS versus non-IBS patients, could potentially guide the use of psychiatric treatments in patients with IBS and comorbidities. Fifth, we could not determine the indications for tests and treatments, including colorectal cancer screening and surveillance. Sixth, we did not gather information on general health care–seeking patterns for use as a covariate in our analyses or total number of visits before and after IBS diagnosis. Specifically, we did not gather data on the total number of contacts per patient in the KPNC system, and it is possible that some of the differences between patients diagnosed by a gastroenterologist versus nongastroenterologist could reflect differences in the opportunities to have tests, diagnoses, and treatments. Finally, no information was available on the use of nonprescription medication, including probiotic preparations.
      • Marteau P.
      Probiotics in functional intestinal disorders and IBS: proof of action and dissecting the multiple mechanisms.
      • Quigley E.M.
      The efficacy of probiotics in IBS.
      • Spiller R.
      Probiotics: an ideal anti-inflammatory treatment for IBS?.
      In conclusion, in this large observational study, the majority of IBS diagnoses were made by generalists and usually without preceding lower endoscopy. Other chronic pain syndromes and psychiatric comorbidities were significantly more common in patients with IBS than in controls, and subsequent diagnosis of another gastrointestinal illness was rare. Patients with IBS demonstrated uniformly higher rates of medical testing than controls as well as higher rates of all types of abdominal and pelvic surgical interventions. Psychiatric medications were used in a majority of IBS patients but usually before IBS diagnosis. Our study provides a detailed accounting of the diagnosis and management of IBS across the spectrum of care in a large population in general medical practice.

      References

        • Spiegel B.M.
        The burden of IBS: looking at metrics.
        Curr Gastroenterol Rep. 2009; 11: 265-269
        • Sandler R.S.
        • Everhart J.E.
        • Donowitz M.
        • et al.
        The burden of selected digestive diseases in the United States.
        Gastroenterology. 2002; 122: 1500-1511
        • Longstreth G.F.
        • Thompson W.G.
        • Chey W.D.
        • et al.
        Functional bowel disorders.
        Gastroenterology. 2006; 130: 1480-1491
        • Ford A.C.
        • Chey W.D.
        • Talley N.J.
        • et al.
        Yield of diagnostic tests for celiac disease in individuals with symptoms suggestive of irritable bowel syndrome: systematic review and meta-analysis.
        Arch Intern Med. 2009; 169: 651-658
        • Jadallah K.A.
        • Khader Y.S.
        Celiac disease in patients with presumed irritable bowel syndrome: a case-finding study.
        World J Gastroenterol. 2009; 15: 5321-5325
        • Zwolińska-Wcisło M.
        • Galicka-Latała D.
        • Rozpondek P.
        • et al.
        [Frequency of celiac disease and irritable bowel syndrome coexistance and its influence on the disease course].
        Przegl Lek. 2009; 66: 126-129
        • Cash B.D.
        • Schoenfeld P.
        • Chey W.D.
        The utility of diagnostic tests in irritable bowel syndrome patients: a systematic review.
        Am J Gastroenterol. 2002; 97: 2812-2819
        • Korkut E.
        • Bektas M.
        • Oztas E.
        • et al.
        The prevalence of celiac disease in patients fulfilling Rome III criteria for irritable bowel syndrome.
        Eur J Intern Med. 2010; 21: 389-392
        • Spiller R.
        • Aziz Q.
        • Creed F.
        • et al.
        Guidelines on the irritable bowel syndrome: mechanisms and practical management.
        Gut. 2007; 56: 1770-1798
        • Brandt L.J.
        • Chey W.D.
        • Foxx-Orenstein A.E.
        • et al.
        An evidence-based position statement on the management of irritable bowel syndrome.
        Am J Gastroenterol. 2009; 104: S1-S35
        • Halpert A.
        • Dalton C.B.
        • Diamant N.E.
        • et al.
        Clinical response to tricyclic antidepressants in functional bowel disorders is not related to dosage.
        Am J Gastroenterol. 2005; 100: 664-671
        • Ford A.C.
        • Talley N.J.
        • Schoenfeld P.S.
        • et al.
        Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and meta-analysis.
        Gut. 2009; 58: 367-378
        • Drossman D.A.
        • Toner B.B.
        • Whitehead W.E.
        • et al.
        Cognitive-behavioral therapy versus education and desipramine versus placebo for moderate to severe functional bowel disorders.
        Gastroenterology. 2003; 125: 19-31
        • Ladabaum U.
        • Sharabidze A.
        • Levin T.R.
        • et al.
        Citalopram provides little or no benefit in nondepressed patients with irritable bowel syndrome.
        Clin Gastroenterol Hepatol. 2010; 8: 42-48
        • Talley N.J.
        • Kellow J.E.
        • Boyce P.
        • et al.
        Antidepressant therapy (imipramine and citalopram) for irritable bowel syndrome: a double-blind, randomized, placebo-controlled trial.
        Dig Dis Sci. 2008; 53: 108-115
        • Friedrich M.
        • Grady S.E.
        • Wall G.C.
        Effects of antidepressants in patients with irritable bowel syndrome and comorbid depression.
        Clin Ther. 2010; 32: 1221-1233
        • Rahimi R.
        • Nikfar S.
        • Rezaie A.
        • et al.
        Efficacy of tricyclic antidepressants in irritable bowel syndrome: a meta-analysis.
        World J Gastroenterol. 2009; 15: 1548-1553
        • Longstreth G.F.
        Avoiding unnecessary surgery in irritable bowel syndrome.
        Gut. 2007; 56: 608-610
        • Longstreth G.F.
        • Yao J.F.
        Irritable bowel syndrome and surgery: a multivariable analysis.
        Gastroenterology. 2004; 126: 1665-1673
        • Lu C.L.
        • Liu C.C.
        • Fuh J.L.
        • et al.
        Irritable bowel syndrome and negative appendectomy: a prospective multivariable investigation.
        Gut. 2007; 56: 655-660
        • Johannson A.
        • Farup G.
        • Bracco A.
        • et al.
        How does comorbidity affect cost of health care in patients with irritable bowel syndrome?.
        BMC Gastroenterol. 2010; 31: 1-6
        • Spiegel B.
        • Kanwal F.
        • Naliboff B.
        • et al.
        The impact of somatization on the use of gastrointestinal health-care resources in patients with irritable bowel syndrome.
        Am J Gastroenterol. 2005; 100: 21-37
        • Spiegel B.
        • Farid M.
        • Esrailian E.
        • et al.
        Is irritable bowel syndrome a diagnosis of exclusion?.
        Am J Gastroenterol. 2010; 105: 848-858
        • Talley N.J.
        Unnecessary abdominal and back surgery in irritable bowel syndrome: time to stem the flood now?.
        Gastroenterology. 2004; 126: 1899-1903
        • Walker E.A.
        • Katon W.J.
        • Jemelka R.P.
        • et al.
        Comorbidity of gastrointestinal complaints, depression, and anxiety in the Epidemiologic Catchment Area (ECA) Study.
        Am J Med. 1992; 92: 26S-30S
        • Thijssen A.Y.
        • Jonkers D.M.
        • Leue C.
        • et al.
        Dysfunctional cognitions, anxiety and depression in irritable bowel syndrome.
        J Clin Gastroenterol. 2010; 44: e236-e241
        • Drossman D.A.
        • Camilleri M.
        • Mayer E.A.
        • et al.
        AGA technical review on irritable bowel syndrome.
        Gastroenterology. 2002; 123: 2108-2131
        • Whitehead W.E.
        • Palsson O.
        • Jones K.R.
        Systematic review of the comorbidity of irritable bowel syndrome with other disorders: what are the causes and implications?.
        Gastroenterology. 2002; 122: 1140-1156
        • Vandvik P.O.
        • Lydersen S.
        • Farup P.G.
        Prevalence, comorbidity and impact of irritable bowel syndrome in Norway.
        Scand J Gastroenterol. 2006; 41: 650-656
        • Cole J.
        • Rothman K.
        • Cabral H.
        • et al.
        Fibromyalgia and depression among people with IBS: a prevalence study.
        BMC Gastroenterol. 2006; 26: 1-8
        • Zaman M.
        • Chavez N.
        • Krueger R.
        • et al.
        Extra-intestinal symptoms in patients with irritable bowel syndrome (IBS).
        Gastroenterology. 2001; 120: A636
        • Jones K.
        • Palsson O.
        • Levy R.
        • et al.
        Comorbid disorders and symptoms in irritable bowel syndrome (IBS) compared to other gastroenterology patients.
        Gastroenterology. 2001; 120: A66
        • Maxton D.G.
        • Morris J.
        • Whorwell P.J.
        More accurate diagnosis of irritable bowel syndrome by the use of “non-colonic” symptomatology.
        Gut. 1991; 32: 784-786
        • Kim J.H.
        • Park H.S.
        • Ko S.Y.
        • et al.
        Diabetic factors associated with gastrointestinal symptoms in patients with type 2 diabetes.
        World J Gastroenterol. 2010; 16: 1782-1787
        • Koch C.A.
        • Uwaifo G.I.
        Are gastrointestinal symptoms related to diabetes mellitus and glycemic control?.
        Eur J Gastroenterol Hepatol. 2008; 20: 822-825
        • Ford A.C.
        • Marwaha A.
        • Lim A.
        • et al.
        Systematic review and meta-analysis of the prevalence of irritable bowel syndrome in individuals with dyspepsia.
        Clin Gastroenterol Hepatol. 2010; 8: 401-409
        • Caballero-Plasencia A.M.
        • Sofos-Kontoyannis S.
        • Valenzuela-Barranco M.
        • et al.
        Irritable bowel syndrome in patients with dyspepsia: a community-based study in southern Europe.
        Eur J Gastroenterol Hepatol. 1999; 11: 517-522
        • Wang A.
        • Liao X.
        • Xiong L.
        The clinical overlap between functional dyspepsia and irritable bowel syndrome based on Rome III criteria.
        BMC Gastroenterol. 2008; 43: 1-7
        • Agréus L.
        • Svarsudd K.
        • Nyrén O.
        • et al.
        Irritable bowel syndrome and dyspepsia in the general population: overlap and lack of stability over time.
        Gastroenterology. 1995; 109: 671-680
        • Miller A.R.
        • North C.S.
        • Clouse R.E.
        • et al.
        The association of irritable bowel syndrome and somatization disorder.
        Ann Clin Psychiatry. 2001; 13: 25-30
        • North C.S.
        • Downs D.
        • Clouse R.E.
        • et al.
        The presentation of irritable bowel syndrome in the context of somatization disorder.
        Clin Gastroenterol Hepatol. 2004; 2: 787-795
        • Lydiard R.B.
        • Fossey M.D.
        • Marsh W.
        • et al.
        Prevalence of psychiatric disorders in patients with irritable bowel syndrome.
        Psychosomatics. 1993; 34: 229-234
        • Koloski N.A.
        • Boyce P.M.
        • Talley N.J.
        Somatization an independent psychosocial risk factor for irritable bowel syndrome but not dyspepsia: a population-based study.
        Eur J Gastroenterol Hepatol. 2006; 18: 1101-1109
        • Aaron L.
        • Burke M.
        • Buchwald D.
        Overlapping conditions among patients with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder.
        Arch Intern Med. 2000; 160: 221-227
        • Choung R.S.
        • Herrick L.M.
        • Locke 3rd, G.R.
        • et al.
        Irritable bowel syndrome and chronic pelvic pain: a population-based study.
        J Clin Gastroenterol. 2010; 44: 696-701
        • Walker E.A.
        • Gelfand A.N.
        • Gelfand M.D.
        • et al.
        Chronic pelvic pain and gynecological symptoms in women with irritable bowel syndrome.
        J Psychosom Obstet Gynaecol. 1996; 17: 39-46
        • Marteau P.
        Probiotics in functional intestinal disorders and IBS: proof of action and dissecting the multiple mechanisms.
        Gut. 2010; 59: 285-286
        • Quigley E.M.
        The efficacy of probiotics in IBS.
        J Clin Gastroenterol. 2008; 42: S85-S90
        • Spiller R.
        Probiotics: an ideal anti-inflammatory treatment for IBS?.
        Gastroenterology. 2005; 128: 783-785