Carol T. Van Dyke

Epidemiology of colonic symptoms and the irritable bowel syndrome

Functional gastrointestinal disease is believed to be very common, but reports of its prevalence have not usually evaluated random community samples, and validated questionnaires have not been used to elicit symptoms. The prevalence of specific colonic symptoms and the irritable bowel syndrome among representative middle-aged whites was determined from a defined population, and the impact of these symptoms on presentation for medical care was measured. An age- and sex-stratified random sample of 1021 residents of Olmsted County, Minnesota, aged 30-64 years, was obtained. All subjects were mailed a valid self-report questionnaire that identified gastrointestinal symptoms and functional gastrointestinal disorders. The response rate was 82% (n = 835). The age- and sex-adjusted prevalence of abdominal pain (more than six times in the prior year) was 26.2 per 100 (95% confidence interval, 23.1-29.2). The prevalence of chronic constipation (hard stools and straining and/or less than 3 stools per week greater than 25% of the time) was 17.4 (95% confidence interval, 14.8-20.0), whereas the prevalence of chronic diarrhea (loose watery stools, and/or greater than 3 stools per day greater than 25% of the time) was 17.9 (95% confidence interval, 15.3-20.5). The prevalence of abdominal pain and disturbed defecation was similar in women and men, except that infrequent defecation and straining at stool were more common in women. Using the Manning symptom criteria to identify irritable bowel syndrome (greater than or equal to 2 of 6 symptoms in those with abdominal pain more than six times in the prior year), the prevalence of irritable bowel syndrome was 17.0 per 100 (95% confidence interval, 14.4-19.6). Overall, 71 persons (9%) reported visiting a physician for abdominal pain or disturbed defecation in the prior year; a subset of variables related to pain severity were the best predictors of health care seeking after adjustment for age and gender. However, these accounted for only 22% of the log likelihood. In conclusion, more than one third of an unselected middle-aged population reported chronic abdominal pain or disturbed defecation, and more than one in six had symptoms compatible with the irritable bowel syndrome. Only a minority had presented for medical evaluation; moreover, the characteristics of the abdominal complaints did not explain the seeking of health care in most cases.

Increasing Incidence of Celiac Disease in a North American Population

OBJECTIVES:The prevalence of celiac disease (CD) varies greatly, potentially because of incomplete ascertainment of cases and small study samples with limited statistical power. Previous reports indicate that the incidence of CD is increasing. We examined the prevalence of CD in a well-defined US county.METHODS:Population-based study in Olmsted County, Minnesota, USA. Using the infrastructure of the Rochester Epidemiology Project, medical, histopathology, and CD serology records were used to identify all new cases of CD in Olmsted County since 2000. Age- and sex-specific and adjusted (to the US white 2000 population) incidence rates for CD were estimated. Clinical presentation at diagnosis was also assessed.RESULTS:Between 2000 and 2010, 249 individuals (157 female or 63%, median age 37.9 years) were diagnosed with CD in Olmsted County. The overall age- and sex-adjusted incidence of CD in the study period was 17.4 (95% confidence interval (CI)=15.2–19.6) per 100,000 person-years, increasing from 11.1 (95% CI=6.8–15.5) in 2000–2001 to 17.3 (95% CI=13.3–21.3) in 2008–2010. The temporal trend in incidence rates was modeled as a two-slope pattern, with the incidence leveling off after 2004. Based on the two classic CD symptoms of diarrhea and weight loss, the relative frequency of classical CD among incident cases decreased over time between 2000 and 2010 (P=0.044).CONCLUSIONS:The incidence of CD has continued to increase in the past decade in a North-American population.

Morbidity and Mortality Among Older Individuals With Undiagnosed Celiac Disease

BACKGROUND & AIMS Outcomes of undiagnosed celiac disease (CD) are unclear. We evaluated the morbidity and mortality of undiagnosed CD in a population-based sample of individuals 50 years of age and older. METHODS Stored sera from a population-based sample of 16,886 Olmsted County, Minnesota, residents 50 years of age and older were tested for CD based on analysis of tissue transglutaminase and endomysial antibodies. A nested case-control study compared serologically defined subjects with CD with age- and sex-matched, seronegative controls. Medical records were reviewed for comorbid conditions. RESULTS We identified 129 (0.8%) subjects with undiagnosed CD in a cohort of 16,847 older adults. A total of 127 undiagnosed cases (49% men; median age, 63.0 y) and 254 matched controls were included in a systematic evaluation for more than 100 potentially coexisting conditions. Subjects with undiagnosed CD had increased rates of osteoporosis and hypothyroidism, as well as lower body mass index and levels of cholesterol and ferritin. Overall survival was not associated with CD status. During a median follow-up period of 10.3 years after serum samples were collected, 20 cases but no controls were diagnosed with CD (15.2% Kaplan-Meier estimate at 10 years). CONCLUSIONS With the exception of reduced bone health, older adults with undiagnosed CD had limited comorbidity and no increase in mortality compared with controls. Some subjects were diagnosed with CD within a decade of serum collection, indicating that although most cases of undiagnosed CD are clinically silent, some result in symptoms. Undiagnosed CD can confer benefits and liabilities to older individuals.

Celiac disease in type 1 diabetes mellitus in a North American community: prevalence, serologic screening, and clinical features.

OBJECTIVES To estimate the prevalence of cellac disease (CD) in pediatric and adult type 1 diabetes melitus in a defined population and to describe clinical features and HLA class II genotypes predictive of CD in screened patients with type 1 diabetes. PATIENTS AND METHODS All residents of Olmsted County, Minnesota, with type 1 diabetes mellitus on the prevalence date January 1, 2001, were identified with the use of an established medical records linkage system (Rochester Epidemiology Project) and defined clinical criteria. Consenting patients underwent serologic screening with endomyslal antibody and tissue transglutaminase antibody testing and Intestinal biopsies to confirm the diagnosis of CD. A subset of screened patients also underwent HLA class II genotyping. Quality-of-life screening (Medical Outcomes Study 36-Item Short-Form Health Survey) was completed in a subset of patients at the time of serologic screening. RESULTS Overall, 392 Olmsted County residents with type 1 diabetes on January 1, 2001, were Identified. A total of 158 patients with type 1 diabetes were tested, representing 40% (158/392) of the enumerated diabetic population, and 11 had biopsy-proven CD for an estimated point prevalence of 7.0% (95% confidence Interval, 3.5%-12.1%). Most CD-positive diabetic patients were asymptomatic and expressed an at-risk CD haplotype with at least one of but not both HLA DQ2 or DQ8. CONCLUSIONS Celiac disease Is not rare In North American patients with type 1 diabetes, and most CD-positive diabetic patients are asymptomatic Irrespective of age at screening.

Effects of multidisciplinary education on outcomes in patients with irritable bowel syndrome.

BACKGROUND & AIMS The impact of education on irritable bowel syndrome (IBS) is not well known. This study evaluated the effect of a onetime group education program on patient-based outcomes in IBS. METHODS All adults referred by Mayo Clinic physicians to the Gastroenterology Division with a diagnosis of IBS between May 1997 and March 1998 were asked to participate. Questionnaires were administered at baseline and 6 months. Symptom resolution, change in pain severity, quality of life, Health-Promoting Lifestyle Profile score, overall patient satisfaction, and health care utilization were compared among those patients who attended the multidisciplinary class and those who did not. RESULTS Of the 506 patients approached, 403 (80%) agreed to participate. The clinical diagnosis was confirmed in 344 patients (85%) on chart review; 211 patients (61%) subsequently completed a follow-up questionnaire. Overall, 29% of class attendees who met Rome criteria for IBS at baseline no longer met Rome criteria at follow-up, compared with 7% of nonattendees. By multivariate analysis, class attendance predicted higher odds of not meeting Rome criteria at follow-up in individuals meeting Rome criteria at baseline (odds ratio, 7.91; 95% confidence interval, 0.97-64.41) than in nonattendees, but the opposite effect was seen with class attendance in those not meeting Rome criteria at baseline. This interaction between baseline Rome status and class attendance was significant (P < 0.05). Class attendance was associated with improvement in Health-Promoting Lifestyle Profile scores (P < 0.05) but not with change in pain, quality of life, satisfaction, or health care utilization. CONCLUSIONS A onetime, multidisciplinary class for patients with IBS was associated with improvement in symptoms and health-promoting lifestyle behavior.

Capsule endoscopy in nonresponsive celiac disease.

BACKGROUND Nonresponsive celiac disease (CD) is defined by persistent or recurrent symptoms, common after treatment with a gluten-free diet (GFD). OBJECTIVE To evaluate the utility of capsule endoscopy (CE) in nonresponsive CD. DESIGN Case-control study. SETTING Tertiary-care center. PATIENTS Forty-two consecutive patients with nonresponsive CD and 84 age- and sex-matched CD-free controls who underwent CE were included. In addition, capsules taken after treatment with a GFD were retrospectively evaluated in 30 patients with uncomplicated CD. INTERVENTION CE. MAIN OUTCOME MEASUREMENTS Diagnostic accuracy of CE for the detection of mucosal abnormalities in nonresponsive CD. RESULTS Macroscopic features of villous atrophy were detected in 13 of 42 patients (31%) with nonresponsive CD compared with none among 84 CD-free controls and 14 of 30 patients (47%) with uncomplicated CD. Among nonresponsive CD cases, the overall sensitivity and specificity of CE for the detection of any degree of villous atrophy as graded by histology were 56% and 85%, respectively. Single or multiple erosions/ulcerations of the gut were observed in 19% of nonresponsive CD patients, 18% of CD-free controls, and 31% of patients with uncomplicated CD (P = .35). The presence of erosions/ulcerations was associated with increased aspirin/nonsteroidal anti-inflammatory drug use in nonresponsive CD (P =.05). Two severe complications (ulcerative jejunitis and adenocarcinoma) were detected by CE in nonresponsive CD. LIMITATIONS Single-center, retrospective study. CONCLUSIONS Mucosal abnormalities were observed by CE in patients with both nonresponsive CD and uncomplicated CD. CE can detect severe complications in patients with nonresponsive CD.

Patients With Celiac Disease Are Not Followed Up Adequately

BACKGROUND & AIMS Adherence to a gluten-free diet is the only effective treatment for celiac disease. It has been recommended that patients be followed up, make regular visits to the clinic, and undergo serologic analysis for markers of celiac disease, although a follow-up procedure has not been standardized. We determined how many patients with celiac disease are actually followed up. METHODS We collected data on 122 patients with biopsy-proven celiac disease, diagnosed between 1996 and 2006 in Olmsted County, Minnesota (70% women; median age, 42 y), for whom complete medical records and verification of residency were available. We determined the frequency at which patients received follow-up examinations, from 6 months to 5 years after diagnosis. The Kaplan-Meier method was used to estimate event rates at 1 and 5 years. Patients were classified according to categories of follow-up procedures recommended by the American Gastroenterological Association (AGA). RESULTS We estimated that by 1 and 5 years after diagnosis with celiac disease, 41.0% and 88.7% of the patients had follow-up visits, 33.6% and 79.8% were assessed for compliance with a gluten-free diet, 3.3% and 15.8% met with a registered dietitian, 2.5% and 18.1% had an additional intestinal biopsy, and 22.1% and 65.6% received serologic testing for markers of celiac disease, respectively. Among 113 patients (93%) who were followed up for more than 4 years, only 35% received follow-up analyses that were consistent with AGA recommendations. CONCLUSIONS Patients with celiac disease are not followed up consistently. Follow-up examinations often are inadequate and do not follow AGA recommendations. Improving follow-up strategies for patients with celiac disease could improve management of this disease.

Human leukocyte antigen genetics and clinical features of self-treated patients on a gluten-free diet.

Background and Aims: Increasingly, people start a gluten-free diet (GFD) without a clear celiac disease (CD) diagnosis. Human leukocyte antigen (HLA) genotyping is useful in ruling out CD in patients with equivocal results of serologic testing or small-bowel biopsy (SBB), but its utility and the clinical features of patients on self-treated GFD (ST-GFD) are largely unknown. Methods: Retrospective study of single tertiary care center cohort compared 137 patients on ST-GFD and 443 patients with well-defined CD. We compared HLA genotype, symptoms, serologic and SBB results, and response to GFD between the 2 groups. Analysis used univariate logistic regression modeling, adjusted for age and sex. Results: Patients with ST-GFD presented more often with diarrhea (P<0.001), abdominal distention (P<0.001), flatulence (P=0.002), cramping (P=0.02), itchy skin (P=0.02), oral inflammation (P=0.04), and constipation (P=0.01) and less often with anemia (P<0.001) or malaise (P=0.02) than CD patients. In addition, 41% did not carry DQ2.5 and DQ8 versus 6% of CD patients (P<0.001). Only 2% of ST-GFD patients had SBB clearly consistent with CD. Family history of CD showed no difference between groups (P=0.77). Although CD patients had a statistically higher rate of GFD benefit, both groups had a high responsiveness rate (98% vs. 94%; P=0.03). Conclusions: HLA genotyping is useful in evaluating patients on an ST-GFD. Although confirmed CD is rare in self-treated patients, most still report benefit from GFD regardless of DQ2 and DQ8 status. Nonceliac gluten sensitivity may play a role.

A questionnaire for the assessment of biliary symptoms.

OBJECTIVES:Gallstone disease is common and causes high health care costs, but a measure of symptomatic biliary disease for outcome studies is lacking. We aimed to develop a reproducible, valid, discriminative, disease-specific measure of biliary symptoms.METHODS:We created the self-report Biliary Symptoms Questionnaire (BSQ) by combining possible biliary symptoms with validated items for gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), and other disorders. We developed the final version through an iterative process and assessed reproducibility by the test–retest method, concurrent validity by comparing BSQ responses with symptoms obtained by structured interview, and discriminative validity by comparing BSQ-based diagnoses of biliary symptoms, GERD, and IBS with patients’ final diagnoses. A shortened version (sBSQ) also underwent reproducibility testing.RESULTS:A total of 245 outpatients (mean age, 55.2 yr; 61% female) participated. Median completion times for the BSQ and sBSQ were 36 and 10 min, respectively. For the BSQ, median κ values were 0.65 (range −0.03 to 0.95) for reproducibility and 0.61 (range 0.15–0.95) for concurrent validity. Using BSQ responses, investigators distinguished IBS and GERD 79–90% of the time. For the sBSQ, the median κ value for reproducibility was 0.72 (range 0.32–0.86).CONCLUSIONS:The BSQ is reproducible and has good concurrent and discriminative validity for biliary symptoms. The abridged sBSQ has good reproducibility. These instruments may be useful in future outcome studies.

Determination of B-Cell Epitopes in Patients with Celiac Disease: Peptide Microarrays.

Background Most antibodies recognize conformational or discontinuous epitopes that have a specific 3-dimensional shape; however, determination of discontinuous B-cell epitopes is a major challenge in bioscience. Moreover, the current methods for identifying peptide epitopes often involve laborious, high-cost peptide screening programs. Here, we present a novel microarray method for identifying discontinuous B-cell epitopes in celiac disease (CD) by using a silicon-based peptide array and computational methods. Methods Using a novel silicon-based microarray platform with a multi-pillar chip, overlapping 12-mer peptide sequences of all native and deamidated gliadins, which are known to trigger CD, were synthesized in situ and used to identify peptide epitopes. Results Using a computational algorithm that considered disease specificity of peptide sequences, 2 distinct epitope sets were identified. Further, by combining the most discriminative 3-mer gliadin sequences with randomly interpolated3- or 6-mer peptide sequences, novel discontinuous epitopes were identified and further optimized to maximize disease discrimination. The final discontinuous epitope sets were tested in a confirmatory cohort of CD patients and controls, yielding 99% sensitivity and 100% specificity. Conclusions These novel sets of epitopes derived from gliadin have a high degree of accuracy in differentiating CD from controls, compared with standard serologic tests. The method of ultra-high-density peptide microarray described here would be broadly useful to develop high-fidelity diagnostic tests and explore pathogenesis.