Lucinda A. Harris

A Novel Histologic Scoring System to Evaluate Mucosal Biopsies From Patients With Eosinophilic Esophagitis

BACKGROUND & AIMS Eosinophilic esophagitis (EoE) is characterized by medically/surgically-resistant gastroesophageal reflux symptoms and dense squamous eosinophilia. Studies suggest that histologic assessment of esophageal eosinophilia alone cannot reliably separate patients with EoE from those with gastroesophageal reflux disease (GERD). Our goal was to develop an assay to identify EoE patients and perhaps differentiate EoE from other causes of esophageal eosinophilia. METHODS A monoclonal antibody specific for an eosinophil secondary granule protein (eosinophil peroxidase [EPX]) was developed and shown to specifically identify intact eosinophils and detect eosinophil degranulation in formalin-fixed specimens. A histopathologic scoring algorithm was developed to analyze data from patient evaluations; the utility of this algorithm was assessed by using archived esophageal tissues from patients with known diagnoses of EoE and GERD as well as controls from 2 tertiary care centers. RESULTS Intraobserver/interobserver blinded evaluations demonstrated a significant difference (P < .001) between scores of samples taken from control subjects, from patients with esophageal eosinophilia who had a diagnosis of EoE, and from patients with GERD (P < .001). This algorithm also was able to identify patients whose clinical course was suggestive of a diagnosis of EoE, but that nonetheless failed to reach the critical threshold number of > or =15 eosinophils in a high-power (40x) microscopy field. CONCLUSIONS A novel immunohistochemical scoring system was developed to address an unmet medical need to differentiate histologic specimens from patients with EoE relative to those with GERD. The availability of a unique anti-EPX-specific monoclonal antibody, combined with the ease/rapidity of this staining method and scoring system, will provide a valuable strategy for the assessment of esophageal eosinophilia.

Incidence of Ischemic Colitis and Serious Complications of Constipation Among Patients Using Alosetron: Systematic Review of Clinical Trials and Post-Marketing Surveillance Data

BACKGROUND:Ischemic colitis and serious complications of constipation have been reported in association with the use of alosetron, which is approved for women with severe diarrhea-predominant IBS who have failed conventional therapies. This systematic review calculated the incidence of these adverse events in alosetron-using patients in clinical trials and post-marketing surveillance.METHODS:A panel of experts in epidemiology and functional bowel disorders reviewed clinical trial report forms and FDA MedWatch forms of each reported case of ischemic colitis or serious complications of constipation. Experts were blinded about whether patients used alosetron or placebo. Using pre-specified criteria, experts rated the likelihood of an accurate diagnosis and an association between medication use and adverse events. Cases that were not consistent with the reported diagnosis or not possibly associated with medication use were eliminated from calculation of incidence rates of adverse events.RESULTS:Pooled data from clinical trials indicate an increased rate of ischemic colitis among alosetron-using patients compared to placebo-using patients (0.15%vs 0.0%, respectively, p= 0.03), but there was no significant difference in the rate of serious complications of constipation. All (19/19) alosetron-using patients with ischemic colitis had reversible colitis without long-term sequelae. Based on post-marketing surveillance data, the post-adjudication rate of ischemic colitis is 1.1 per 1,000 patient-years of alosetron use and the rate of serious complications of constipation is 0.66 per 1,000 patient-years of alosetron use.CONCLUSION:The incidence of ischemic colitis and serious complications of constipation is very low and is rarely associated with long-term sequelae or serious morbidity.

A randomized, double-blind study of larazotide acetate to prevent the activation of celiac disease during gluten challenge.

OBJECTIVES:In patients with celiac disease, enteropathy is caused by the entry of gluten peptides into the lamina propria of the intestine, in which their immunogenicity is potentiated by tissue transglutaminase (tTG) and T-helper type 1–mediated immune responses are triggered. Tight junction disassembly and paracellular permeability are believed to have an important role in the transport of gluten peptides to the lamina propria. Larazotide acetate is a tight-junction regulator peptide that, in vitro, prevents the opening of intestinal epithelial tight junctions. The aim of this study was to evaluate the efficacy and tolerability of larazotide acetate in protecting against gluten-induced intestinal permeability and gastrointestinal symptom severity in patients with celiac disease.METHODS:In this dose-ranging, placebo-controlled study, 86 patients with celiac disease controlled through diet were randomly assigned to larazotide acetate (0.25, 1, 4, or 8 mg) or placebo three times per day with or without gluten challenge (2.4 g/day) for 14 days. The primary efficacy outcome was the urinary lactulose/mannitol (LAMA) fractional excretion ratio. Secondary endpoints included gastrointestinal symptom severity, quality-of-life measures, and antibodies to tTG.RESULTS:LAMA measurements were highly variable in the outpatient setting. The increase in LAMA ratio associated with the gluten challenge was not statistically significantly greater than the increase in the gluten-free control. Among patients receiving the gluten challenge, the difference in the LAMA ratios for the larazotide acetate and placebo groups was not statistically significant. However, larazotide acetate appeared to limit gluten-induced worsening of gastrointestinal symptom severity as measured by the Gastrointestinal Symptom Rating Scale at some lower doses but not at the higher dose. Symptoms worsened significantly in the gluten challenge–placebo arm compared with the placebo–placebo arm, suggesting that 2.4 g of gluten per day is sufficient to induce reproducible gluten toxicity. Larazotide acetate was generally well tolerated. No serious adverse events were observed. The most common adverse events were headache and urinary tract infection.CONCLUSIONS:LAMA variability in the outpatient setting precluded accurate assessment of the effect of larazotide acetate on intestinal permeability. However, some lower doses of larazotide acetate appeared to prevent the increase in gastrointestinal symptom severity induced by gluten challenge.

C-reactive protein and high-sensitivity C-reactive protein: An update for clinicians

Abstract The measurement of C-reactive protein (CRP) using both standard and high-sensitivity CRP (hs-CRP) assays is becoming common in clinical practice. This article addresses the causes of CRP elevation and the use of different CRP assays in internal medicine, including cardiology, gastroenterology, rheumatology, infectious diseases, and oncology. We focus on the recent medical literature on the use of hs-CRP in cardiovascular disease risk stratification and management, including updated screening guidelines on the use of hs-CRP, such as those issued in 2009 by the Canadian Cardiovascular Society. We also discuss the Reynolds Risk Score, which incorporates hs-CRP and family history with more standard cardiovascular risk factors (eg, tobacco use, hypertension, and dyslipidemia) and frequently leads to improved recategorization of cardiovascular disease risk levels. As the recently completed Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial indicated that statin therapy decreases the vascular events among persons with elevated hs-CRP by half, even when cholesterol levels are low, the inclusion of information on hs-CRP values with other cardiovascular risk factors may assist physicians in medical decision making for patients.

Performance of the patency capsule compared with nonenteroclysis radiologic examinations in patients with known or suspected intestinal strictures

BACKGROUND The patency capsule (PC) is used before capsule endoscopy (CE) in patients with known or suspected small-bowel (SB) strictures or obstruction (SBO) to avoid CE retention. False-positive PC examination results can occur in patients with delayed transit without obstruction, precluding the use of CE. Radiological tests are another option to evaluate the presence of SBO before CE. OBJECTIVES Comparison of the PC and radiological examinations to detect clinically significant SB strictures. MAIN OUTCOME MEASUREMENTS Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the PC, and radiological tests for detecting significant strictures. RESULTS Forty-two patients underwent a PC study and radiological examinations. Both of the examinations showed similar sensitivity (57% vs 71%; P = 1.00) and specificity (86% vs 97%; P = .22). The receiver-operating characteristic curves evaluating combined sensitivity and specificity were also similar in both the PC and radiological examinations (0.71 vs 0.84, respectively; P = .46). Pooling results from both the PC and radiological tests had the highest sensitivity and NPV (100%, 100%). False-positive results occurred in 5 PC examinations and 1 radiological examination. The PC examination had 3 false-negative results (9%), whereas radiological tests had 2 (6%). LIMITATIONS Retrospective study. CONCLUSIONS The NPV for the PC and radiological tests were not significantly different, suggesting that if findings on either test are negative before CE, the patient will most likely pass the capsule without incident. Radiological tests can be used to minimize PC study false-positive results by confirming or excluding the presence of a significant stricture suspected by the PC and to localize the PC if passage is delayed.

Measuring symptoms in the irritable bowel syndrome: development of a framework for clinical trials

Aliment Pharmacol Ther 2010; 32: 1275–1291

Developing Valid and Reliable Health Utilities in Irritable Bowel Syndrome: Results from The IBS PROOF Cohort

OBJECTIVES:A “utility” is a measure of health-related quality of life (HRQOL) that ranges between 0 (death) and 1 (perfect health). Disease-targeted utilities are mandatory to conduct cost–utility analyses. Given the economic and healthcare burden of irritable bowel syndrome (IBS), cost–utility analyses will play an important role in guiding health economic decision-making. To inform future cost–utility analyses in IBS, we measured and validated the IBS utilities.METHODS:We analyzed data from Rome III IBS patients in the Patient Reported Observed Outcomes and Function (PROOF) Cohort—a longitudinal multi-center IBS registry. At entry, the patients completed a multi-attribute utility instrument (EuroQOL), bowel symptom items, IBS severity measurements (IBS Severity Scale (IBSSS), Functional Bowel Disease Severity Index (FBDSI)), HRQOL indexes (IBS quality-of-life instrument (IBS-QOL), Center for disease control-4 (CDC-4)), and the Worker Productivity Activity Index for IBS (WPAI). We repeated assessments at 3 months.RESULTS:There were 257 patients (79% women; age=43±15 years) at baseline and 85 at 3 months. The mean utilities in patients with severe vs. non-severe IBS were 0.70 and 0.80, respectively (P<0.001). There were no differences in utilities among IBS with constipation (IBS-C), IBS with diarrhea (IBS-D), and mixed IBS (IBS-M) subgroups. EuroQOL utilities correlated with FBDSI (r=0.31; P<0.01), IBSSS (r=0.36; P<0.01), IBS-QOL (r=0.36; P<0.01), CDC-4 (r=0.44; P<0.01), WPAI presenteeism (r=0.16; P<0.01), abdominal pain (r=0.43; P<0.01), and distension (r=0.18; P=0.01). The utilities in patients reporting “considerable relief” of symptoms at 3 months vs. those without considerable relief were 0.78 and 0.73, respectively (P=0.02).CONCLUSIONS:EuroQOL utilities are valid and reliable in IBS. The utility of severe IBS (0.7) is similar to Class III congestive heart failure and rheumatoid arthritis. These validated utilities can be employed in future IBS cost–utility analyses.

Impact of Anal Incontinence on Psychosocial Function and Health-Related Quality of Life

The relationship among the frequency of anal incontinence (AI), psychosocial factors, and health-related quality of life (HRQOL) was evaluated. Consecutive patients (n=280) completed a bowel symptom questionnaire, the Symptom Checklist 90—Revised (SCL 90-R), and an assessment of HRQOL. Group 1 had no incontinence, Group 2 had AI less than once per week, and Group 3 experienced AI more than once per week. Multivariate analyses were used to evaluate the relationship among symptoms, the SCL-90-R subscales, and HRQOL. Group 3 reported more frequent stools than the other groups. Significant psychological distress was present in both incontinent groups compared to Group 1 (P=0.002). A reduction in overall HRQOL was also seen in the incontinent groups. Depression was inversely correlated with QOL-Satisfaction and QOL-Ratings and positively correlated with QOL-Interference. AI was associated with impaired psychosocial function and decreased HRQOL. The frequency of AI was associated with increased HRQOL-Interference, but minimally with the degree of psychosocial impairment.

Capsule Endoscopy in Patients with Implantable Electromedical Devices is Safe

Background and Study Aims. The presence of an implantable electromechanical cardiac device (IED) has long been considered a relative contraindication to the performance of video capsule endoscopy (CE). The primary aim of this study was to evaluate the safety of CE in patients with IEDs. A secondary purpose was to determine whether IEDs have any impact on images captured by CE. Patients and Methods. A retrospective chart review of all patients who had a capsule endoscopy at Mayo Clinic in Scottsdale, AZ, USA, or Rochester, MN, USA, (January 2002 to June 2010) was performed to identify CE studies done on patients with IEDs. One hundred and eighteen capsule studies performed in 108 patients with IEDs were identified and reviewed for demographic data, method of preparation, and study data. Results. The most common indications for CE were obscure gastrointestinal bleeding (77%), anemia (14%), abdominal pain (5%), celiac disease (2%), diarrhea (1%), and Crohns disease (1%). Postprocedure assessments did not reveal any detectable alteration on the function of the IED. One patient with an ICD had a 25-minute loss of capsule imaging due to recorder defect. Two patients with LVADs had interference with capsule image acquisition. Conclusions. CE did not interfere with IED function, including PM, ICD, and/or LVAD and thus appears safe. Additionally, PM and ICD do not appear to interfere with image acquisition but LVAD may interfere with capsule images and require that capsule leads be positioned as far away as possible from the IED to assure reliable image acquisition.

Celiac disease: clinical, endoscopic, and histopathologic review

Celiac disease, also known as celiac sprue, nontropical sprue, and gluten-sensitive enteropathy, is a chronic immune-mediated disorder that occurs in genetically predisposed populations. Patients affected by the disease may be asymptomatic or manifest classic malabsorption symptoms of abdominal pain, bloating, weight loss, diarrhea, and steatorrhea after gluten ingestion (and related derivatives found in other grains). The astute clinician must be aware of a more subtle GI picture as well as non-GI signs and symptoms (eg, iron-deficiency anemia, abnormal liver function tests, type 1 diabetes mellitus, and gluten ataxia). Diagnosis and screening begin with the use of serologic tests: IgA anti-tissue transglutaminase (tTG), IgA antiendomysial antibodies (EMAs), and serum IgA level. Duodenal biopsy, still considered by many as the criterion necessary for diagnosis, demonstrates the pathologic findings of small intestinal villous atrophy, intraepithelial lymphocytosis, and crypt hyperplasia that occur on exposure to dietary gluten. These changes exhibit improvement after withdrawal of gluten from the diet. Resolution of clinical symptoms after initiation of gluten-free diet is considered to be part of the diagnostic picture. Genetic tests revealing permissive haplotypes may be helpful in confirming the diagnosis as well as identifying susceptible individuals. Celiac disease remains a complex clinicopathologic diagnosis. This review discusses the clinical, endoscopic, and pathologic features of celiac disease, with an emphasis on the importance of clinician and pathologist communication.