Karthik Ravi

Inflammatory bowel disease in the setting of autoimmune pancreatitis.

Background: Despite scattered case reports, the prevalence of inflammatory bowel disease (IBD) in patients with autoimmune pancreatitis (AIP) is unknown. We sought to better characterize the putative association between the conditions. Methods: Medical records of 71 patients meeting accepted criteria for AIP were reviewed to identify those with endoscopic and histological evidence of IBD. Colon samples in patients with both AIP and IBD were immunostained to identify IgG4‐positive cells. Results: Four patients with AIP (5.6%) had a diagnosis of IBD: 3 had ulcerative colitis (UC) and 1 had Crohns disease (CD). The diagnosis of IBD preceded or was simultaneous to that of AIP. Two AIP‐UC patients treated for AIP with prednisone had a recurrence of AIP, and 1 required 6‐mercaptopurine for long‐term corticosteroid‐sparing treatment. Two AIP‐IBD patients underwent Whipple resections, and 1 had recurrent AIP. All 3 patients with UC presented with pancolitis, and 2 required colectomy. Colon samples from 1 patient with UC and 1 patient with CD were available for review. Increased numbers of IgG4‐positive cells (10 per high‐power field) were noted on the colon sample from the patient with UC. Conclusions: Almost 6% of patients with proven AIP had a diagnosis of IBD, compared to a prevalence of ≈0.4%–0.5% in the general population, potentially implying a 12–15‐fold increase in risk. Patients with both AIP and IBD may have increased extent and severity of IBD. The finding of IgG4‐positive cells on colon biopsy suggests that IBD may represent an extrapancreatic manifestation of AIP. (Inflamm Bowel Dis 2009)

NORMAL VALUES FOR HIGH-RESOLUTION ANORECTAL MANOMETRY IN HEALTHY WOMEN: EFFECTS OF AGE AND SIGNIFICANCE OF RECTOANAL GRADIENT

OBJECTIVES:High-resolution manometry (HRM) is used to measure anal pressures in clinical practice but normal values have not been available. Although rectal evacuation is assessed by the rectoanal gradient during simulated evacuation, there is substantial overlap between healthy people and defecatory disorders, and the effects of age are unknown. We evaluated the effects of age on anorectal pressures and rectal balloon expulsion in healthy women.METHODS:Anorectal pressures (HRM), rectal sensation, and balloon expulsion time (BET) were evaluated in 62 asymptomatic women ranging in age from 21 to 80 years (median age 44 years) without risk factors for anorectal trauma. In total, 30 women were aged <50 years.RESULTS:Age is associated with lower (r=−0.47, P<0.01) anal resting (63 (5) (≥50 years), 88 (3) (<50 years), mean (s.e.m.)) but not squeeze pressures; higher rectal pressure and rectoanal gradient during simulated evacuation (r=0.3, P<0.05); and a shorter (r=−0.4, P<0.01) rectal BET (17 (9) s (≥50 years) vs. 31 (10) s (<50 years)). Only 5 women had a prolonged (>60 s) rectal BET but 52 had higher anal than rectal pressures (i.e., negative gradient) during simulated evacuation. The gradient was more negative in younger (−41 (6) mm Hg) than older (−12 (6) mm Hg) women and negatively (r=−0.51, P<0.0001) correlated with rectal BET but only explained 16% of the variation in rectal BET.CONCLUSIONS:These observations provide normal values for anorectal pressures by HRM. Increasing age is associated with lower anal resting pressure, a more positive rectoanal gradient during simulated evacuation, and a shorter BET in asymptomatic women. Although the rectoanal gradient is negatively correlated with rectal BET, this gradient is negative even in a majority of asymptomatic women, undermining the utility of a negative gradient for diagnosing defecatory disorders by HRM.

Phenotypic Variation of Colonic Motor Functions in Chronic Constipation

BACKGROUND & AIMS Colonic motor disturbances in chronic constipation (CC) are heterogeneous and incompletely understood; the relationship between colonic transit and motor activity is unclear. We sought to characterize the phenotypic variability in chronic constipation. METHODS Fasting and postprandial colonic tone and phasic activity and pressure-volume relationships were assessed by a barostat manometric assembly in 35 healthy women and 111 women with CC who had normal colon transit (NTC; n = 25), slow transit (STC; n = 19), and defecatory disorders with normal (DD-normal; n = 34) or slow transit (DD-slow; n = 33). Logistic regression models assessed whether motor parameters could discriminate among these groups. Among CC, phenotypes were characterized by principal components analysis of these measurements. RESULTS Compared with 10th percentile values in healthy subjects, fasting and/or postprandial colonic tone and/or compliance were reduced in 40% with NTC, 47% with STC, 53% with DD-normal, and 42% with DD-slow transit. Compared with healthy subjects, compliance was reduced (P <or= .05) in isolated STC and DD but not in NTC. Four principal components accounted for 85% of the total variation among patients: factors 1 and 2 were predominantly weighted by fasting and postprandial colonic phasic activity and tone, respectively; factor 3 by postprandial high-amplitude propagated contractions; and factor 4 by postprandial tonic response. CONCLUSIONS Fasting and/or postprandial colonic tone are reduced, reflecting motor dysfunctions, even in NTC. Colonic motor assessments allow chronic constipation to be characterized into phenotypes. Further studies are needed to evaluate the relationship among these phenotypes, enteric neuropathology, and response to treatment in CC.

Esophageal Diameter Is Decreased in Some Patients With Eosinophilic Esophagitis and Might Increase With Topical Corticosteroid Therapy

BACKGROUND & AIMS The rapid response to topical corticosteroids makes it hard to implicate fibrosis as the cause of dysphagia in patients with eosinophilic esophagitis (EoE). We examined surrogates of esophageal expansion using minimal and maximal esophageal diameter (EDmin and EDmax) in barium swallow examinations. METHODS Eleven patients evaluated at Mayo Clinic, Rochester (8 female, median age 40, median diagnosis 36 months, median symptom duration 132 months) underwent barium esophagrams to determine EDmin and EDmax before and after 6 weeks of topical corticosteroid therapy. We assessed parameter reproducibility (in healthy volunteers), baseline EDmin and EDmax, postcorticosteroid changes in EoE patients, and correlation with clinical response. RESULTS EDmin and EDmax were reproducible, with nonsignificant variance in the 2 esophagrams in control subjects (P = .44 and P = .66, respectively). Baseline EDmax was reduced in EoE at 19 mm (range, 13-26 mm) vs 24 mm (range, 19-29 mm) in controls (P = .004). About 50% of the EoE patients had EDmax and min values within the 10th to 90th percentile of controls (45% and 55%, respectively). Clinical improvement by Mayo Dsyphagia Questionnaire did not correlate with postcorticosteroid luminal change (P = .19 for EDmax; P = .75 for EDmin). Median increases in postcorticosteroid EDmax and EDmin were not statistically significant (P = .15 and .1, respectively). However, they were significant in patients with abnormal baseline EDmax (n = 6; 2 mm; P = .01) and EDmin (n = 5; 3 mm; P = .02). CONCLUSIONS Esophageal diameter is a reproducible parameter that is frequently decreased in EoE, but normal in approximately 50% of patients. Those with narrowing might respond to steroids, but it is unclear if narrowing causes dysphagia.

Endoscopic Mucosal Impedance Measurements Correlate With Eosinophilia and Dilation of Intercellular Spaces in Patients With Eosinophilic Esophagitis

BACKGROUND & AIMS Penetration of the esophageal epithelium by food antigens is an early event in the pathogenesis of eosinophilic esophagitis (EoE), but the precise relationship among eosinophilia, dilated intercellular spaces (DIS), and decreased barrier function is unclear. We investigated the correlation between site-specific mucosal impedance (MI) measurements of ion flux and esophageal histology, and whether MI measurements can be used to distinguish between patients with active and inactive EoE. METHODS MI was measured (in Ω) in 10 patients with active EoE (>15 eosinophils [eos]/high-power field [HPF]) and in 10 with inactive EoE (<15 eos/HPF, as a result of treatment), and mucosal biopsy specimens were collected from 4 esophageal sites (2, 5, 10, and 15 cm above the Z-line). MI also was measured in 10 individuals without esophageal symptoms (controls). MI measurements, eos/HPF, and DIS grade were compared among patients with EoE and controls. RESULTS The esophageal MI values were significantly lower in patients with active EoE (1909 Ω) compared with inactive EoE (4349 Ω) or controls (5530 Ω) (P < .001). Biopsy specimens from 4 patients with active EoE contained fewer than 15 eos/HPF and lower-grade DIS than in patients with active disease. There were significant inverse correlations between MI and eos/HPF (rs = -.584), as well as between MI and DIS (rs = -.531; P < .001). The MI cut-off value of 2300 Ω identified patients with active EoE with 90% sensitivity and 91% specificity, and high-grade DIS with 89% sensitivity and 82% specificity. CONCLUSIONS In patients with EoE, eosinophilia and DIS correlate with MI measurements of ion flux. Endoscopic MI measurement in the esophagus is safe and easy to perform, and can be used to assess activity of diseases such as EoE.

Oesophageal narrowing is common and frequently under-appreciated at endoscopy in patients with oesophageal eosinophilia.

Estimation of the prevalence of oesophageal narrowing and its clinical relevance in patients with oesophageal eosinophilia is probably underestimated by endoscopy.

Diagnosis of esophageal motility disorders: Esophageal pressure topography vs. conventional line tracing

OBJECTIVES:Enhanced characterization of esophageal peristaltic and sphincter function provided by esophageal pressure topography (EPT) offers a potential diagnostic advantage over conventional line tracings (CLT). However, high-resolution manometry (HRM) and EPT require increased equipment costs over conventional systems and evidence demonstrating a significant diagnostic advantage of EPT over CLT is limited. Our aim was to investigate whether the inter-rater agreement and/or accuracy of esophageal motility diagnosis differed between EPT and CLT.METHODS:Forty previously completed patient HRM studies were selected for analysis using a customized software program developed to perform blinded independent interpretation in either EPT or CLT (six pressure sensors) format. Six experienced gastroenterologists with a clinical focus in esophageal disease (attendings) and six gastroenterology trainees with minimal manometry experience (fellows) from three academic centers interpreted each of the 40 studies using both EPT and CLT formats. Rater diagnoses were assessed for inter-rater agreement and diagnostic accuracy, both for exact diagnosis and for correct identification of a major esophageal motility disorder.RESULTS:The total group agreement was moderate (κ=0.57; 95% CI: 0.56–0.59) for EPT and fair (κ=0.32; 0.30–0.33) for CLT. Inter-rater agreement between attendings was good (κ=0.68; 0.65–0.71) for EPT and moderate (κ=0.46; 0.43–0.50) for CLT. Inter-rater agreement between fellows was moderate (κ=0.48; 0.45–0.50) for EPT and poor to fair (κ=0.20; 0.17–0.24) for CLT. Among all raters, the odds of an incorrect exact esophageal motility diagnosis were 3.3 times higher with CLT assessment than with EPT (OR: 3.3; 95% CI: 2.4–4.5; P<0.0001), and the odds of incorrect identification of a major motility disorder were 3.4 times higher with CLT than with EPT (OR: 3.4; 2.4–5.0; P<0.0001).CONCLUSIONS:Superior inter-rater agreement and diagnostic accuracy of esophageal motility diagnoses were demonstrated with analysis using EPT over CLT among our selected raters. On the basis of these findings, EPT may be the preferred assessment modality of esophageal motility.

The digital rectal examination: A multicenter survey of physicians' and students' perceptions and practice patterns

Objectives:The digital rectal examination (DRE) may be underutilized. We assessed the frequency of DREs among a variety of providers and explored factors affecting its performance and utilization.Methods:A total of 652 faculty, fellows, medical residents, and final-year medical students completed a questionnaire about their use of DREs.Results:On average, 41 DREs per year were performed. The yearly number of examinations was associated with years of experience and specialty type. Patient refusal rates were lowest among gastroenterology (GI) faculty and highest among primary-care doctors. Refusal rates were negatively correlated with comfort level of the physician in performing a DRE. More gastroenterologists used sophisticated methods to detect anorectal conditions, and gastroenterologists were more confident in diagnosing them. Confidence in making a diagnosis with a DRE was strongly associated with the number of DREs performed annually.Conclusions:The higher frequencies of performing a DRE, lower refusal rate, degree of comfort, diagnostic confidence, and training adequacy were directly related to level of experience with the examination. Training in DRE technique has diminished and may be lost. The DREs role in medical school and advanced training curricula needs to be re-established.

Increased Numbers of Eosinophils, Rather Than Only Etiology, Predict Histologic Changes in Patients With Esophageal Eosinophilia

BACKGROUND & AIMS It can be a challenge to differentiate individuals with eosinophilic esophagitis (EoE) from those with gastroesophageal reflux disease (GERD). We investigated differences in histologic and eosinophil patterns and numbers of mast cells between patients with these disorders. METHODS We performed histologic analyses and immunohistochemical assays for eosinophil-derived neurotoxin (EDN), major basic protein (MBP), and tryptase, using biopsy samples from 10 patients with GERD (positive results from a pH study and response to proton pump inhibitors), Barretts esophagus, or EoE (negative results from a pH study and positive response to budesonide). Patients were matched for degree of eosinophilia. RESULTS Samples from patients with EoE, GERD, or Barretts esophagus had similar increases in concentrations of eosinophils. Patients with GERD or EoE did not differ in amount of basal zone hyperplasia, microabscesses, spongiosis, eosinophil distribution, maximum eosinophils/high-power field (HPF), or composite histologic scores. Samples from all 3 groups had high levels of EDN and MBP; the levels of eosinophil products were correlated (ρ = 0.93). Extracellular staining for EDN was greater than intracellular staining (2.67 of 3 vs 1.86 of 3); levels tended to be greater in samples from patients with EoE than GERD (P = .05) or Barretts esophagus (P = .06). Detection of EDN correlated with peak numbers of eosinophils/HPF (ρ = 0.6 for intracellular and extracellular staining). Peak numbers of tryptase-positive mast cells/HPF were significantly greater in samples from patients with EoE than GERD or Barretts esophagus (P = .01 and .005, respectively). The Spearman correlation between eosinophil and mast cell density was a ρ value of 0.2. CONCLUSIONS Biopsy samples from patients with GERD and EoE, matched for esophageal eosinophilia, have similar changes in histology and levels of EDN and MBP, whereas mast cells from patients with EoE have higher levels of these products. The presence of esophageal eosinophils, rather than etiology, could be the most important determinant of epithelial response.

Montelukast Does not Maintain Symptom Remission After Topical Steroid Therapy for Eosinophilic Esophagitis

BACKGROUND & AIMS: Montelukast, a cysteinyl leukotriene type‐1 receptor blocker, has been shown in small retrospective studies to reduce symptoms in patients with eosinophilic esophagitis (EoE). We performed a randomized, placebo‐controlled, double‐blind trial to determine whether montelukast maintains symptomatic remission induced by topical steroid therapy in patients with EoE. METHODS: We performed a prospective study of adult patients with EoE (solid‐food dysphagia and a peak esophageal eosinophil count of >20 cells/high‐powered field) enrolled at the Mayo Clinic in Rochester, Minnesota, from April 2008 through February 2015. All patients had been treated previously for at least 6 weeks with a topical steroid until their symptoms were in remission. Steroids were discontinued and patients then were assigned randomly to groups given montelukast (20 mg/day, n = 20) or placebo (n = 21) for 26 weeks (groups were matched for age, sex, history of allergic disease, reflux symptoms, and endoscopic findings of EoE). Study participants were assessed via a structured telephone interview at weeks 2, 4, 8, 12, 16, 20, and 24. Remission was defined as the absence of solid‐food dysphagia. RESULTS: Based on an intention‐to‐treat analysis, after 26 weeks, 40.0% of subjects in the montelukast group and 23.8% in the placebo group were in remission. The odds ratio for remission in the montelukast group was 0.48 (95% confidence interval, 0.10–2.16) (P = .33). No side effects were reported from either group. CONCLUSIONS: In a randomized controlled trial of the ability of montelukast to maintain remission in patients in remission from EoE after steroid therapy, we found montelukast to be well tolerated; 40% of patients remained in remission, but this proportion did not differ significantly from that of the placebo group. ClinicalTrials.gov no: NCT00511316.