Navya D. Kanuri

Serum analysis of tryptophan catabolism pathway: Correlation with Crohn's disease activity

Background: Indoleamine 2,3 dioxygenase‐1 (IDO1) is a tryptophan catabolizing enzyme with immunotolerance‐promoting functions. We sought to determine if increased gut expression of IDO1 in Crohns disease (CD) would result in detectable changes in serum levels of tryptophan and the initial IDO1 pathway catabolite, kynurenine. Methods: Individuals were prospectively enrolled through the Washington University Digestive Diseases Research Center. The Montreal Classification was used for disease phenotyping. Disease severity was categorized by the Physicians Global Assessment. Serum tryptophan and kynurenine were measured by high‐pressure liquid chromatography. IDO1 immunohistochemical staining was performed on formalin‐fixed tissue blocks. Results: In all, 25 CD patients and 11 controls were enrolled. Eight CD patients had serum collected at two different timepoints and levels of disease activity compared. Strong IDO1 expression exists in both the lamina propria and epithelium during active CD compared to controls. Suppressed serum tryptophan levels and an elevated kynurenine/tryptophan (K/T) ratio were found in individuals with active CD as compared to those in remission or the control population. K/T ratios correlated positively with disease activity as well as with C‐reactive protein and erythrocyte sedimentation rate. In the subgroup of CD patients with two serum measurements, tryptophan levels were elevated while kynurenine levels and the K/T ratio lowered as the disease activity lessened. Conclusions: IDO1 expression in CD is associated with lower serum tryptophan and an elevated K/T ratio. These levels may serve as a reasonable objective marker of gut mucosal immune activation and as a surrogate for CD activity. (Inflamm Bowel Dis 2011;)

Vedolizumab Effectiveness and Safety Over the First Year of Use in an IBD Clinical Practice

BACKGROUND AND AIMS Vedolizumab inhibits leucocyte vascular adhesion and migration into the gastrointestinal tract through α4β7 integrin blockade. This agent became available in mid-2014 for the treatment of moderate to severe Crohns disease (CD) and UC (UC). The aim of this study was to assess the patterns of use, effectiveness and safety of vedolizumab in an inflammatory bowel disease (IBD) clinical practice. METHODS Patients beginning vedolizumab were enrolled with informed consent. A prospective cohort was followed with laboratory, disease activity and quality-of-life assessments made during infusion visits up to week 14. Duration of vedolizumab use, mucosal healing and safety were analysed retrospectively for all patients not captured in the prospective component of this study. RESULTS One hundred and two patients started vedolizumab, with 51 patients (30 CD, 21 UC) followed prospectively. The CD patients exhibited a significant decrease in Crohns Disease Activity Index (p = 0.04) and Harvey-Bradshaw index (p < 0.01) by week 14. The UC patients demonstrated improved partial Mayo scores at weeks 6 (p < 0.01) and 14 (p < 0.001). Ninety percent of all CD and UC patients remained on vedolizumab up to week 14. IBD-related quality of life was improved by week 6 in CD and UC cohorts (p = 0.02 and p < 0.01 respectively). Colectomy for lack of response and systemic histoplamosis were notable reasons for early discontinuation of vedolizumab, which was otherwise well tolerated. CONCLUSIONS Vedolizumab was efficacious and a high percentage of patients continued this therapy beyond induction dosing. Observed safety signals may be attributed to the refractory IBD disease state of this early-adopting clinical cohort.

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 impact of abuse and mood on bowel symptoms and health‐related quality of life in irritable bowel syndrome (IBS)

Irritable bowel syndrome (IBS) is a common abdominal pain disorder without an organic explanation. Abuse histories (physical, sexual, emotional) are prevalent in IBS. While abuse relates to mood disorders (depression and anxiety) also common in IBS, the influence of abuse on gastrointestinal (GI) symptoms and health‐related quality of life (HRQOL) and its independence from psychological symptom comorbidity has not been studied.

Genetic variation in the beta-2 adrenergic receptor (ADRB2) predicts functional gastrointestinal diagnoses and poorer health-related quality of life

The beta‐2 adrenergic receptor (ADRB2) is an important target for epinephrine, a neurotransmitter in pain signalling. ADRB2 haplotypes affect receptor expression and ligand response, and have been linked to painful non‐GI disorders.

IDO1 and IDO2 Non-Synonymous Gene Variants: Correlation with Crohn's Disease Risk and Clinical Phenotype

Background Crohns disease (CD) is a chronic inflammatory disease of the gastrointestinal tract. Genetic polymorphisms can confer CD risk and influence disease phenotype. Indoleamine 2,3 dioxygenase-1 (IDO1) is one of the most over-expressed genes in CD and mediates potent anti-inflammatory effects via tryptophan metabolism along the kynurenine pathway. We aimed to determine whether non-synonymous polymorphisms in IDO1 or IDO2 (a gene paralog) are important either as CD risk alleles or as modifiers of CD phenotype. Methods Utilizing a prospectively collected database, clinically phenotyped CD patients (n = 734) and non-IBD controls (n = 354) were genotyped for established IDO1 and IDO2 non-synonymous single nucleotide polymorphisms (SNPs) and novel genetic variants elucidated in the literature. Allelic frequencies between CD and non-IBD controls were compared. Genotype-phenotype analysis was conducted. IDO1 enzyme activity was assessed by calculating the serum kynurenine to tryptophan ratio (K/T). Results IDO1 SNPs were rare (1.7% non-IBD vs 1.1% CD; p = NS) and not linked to Crohns disease diagnosis in this population. IDO1 SNPs did however associate with a severe clinical course, presence of perianal disease, extraintestinal manifestations and a reduced serum K/T ratio during active disease suggesting lower IDO1 function. IDO2 minor allele variants were common and one of them, rs45003083, associated with reduced risk of Crohns disease (p = 0.025). No IDO2 SNPs associated with a particular Crohns disease clinical phenotype. Conclusions This work highlights the functional importance of IDO enzymes in human Crohns disease and establishes relative rates of IDO genetic variants in a US population.

The learning curve for interpretation of oesophageal high‐resolution manometry: a prospective interventional cohort study

High‐resolution manometry has become the preferred choice of oesophagologists for oesophageal motor assessment, but the learning curve among trainees remains unclear.

Opioid medication use in patients with gastrointestinal diagnoses vs unexplained gastrointestinal symptoms in the US Veterans Health Administration

While opioid prescriptions have increased alarmingly in the United States (US), their use for unexplained chronic gastrointestinal (GI) pain (eg, irritable bowel syndrome) carries an especially high risk for adverse effects and questionable benefit.

Coeliac disease screening is suboptimal in a tertiary gastroenterology setting

Background and aims Coeliac disease (CD) is widely prevalent in North America, but case-finding techniques currently used may not be adequate for patient identification. We aimed to determine the adequacy of CD screening in an academic gastroenterology (GI) practice. Methods Consecutive initial visits to a tertiary academic GI practice were surveyed over a 3-month period as a fellow-initiated quality improvement project. All electronic records were reviewed to look for indications for CD screening according to published guidelines. The timing of screening was noted (before or after referral), as well as the screening method (serology or biopsy). Data were analysed to compare CD screening practices across subspecialty clinics. Results 616 consecutive patients (49±0.6 years, range 16–87 years, 58.5% females, 94% Caucasian) fulfilled inclusion criteria. CD testing was indicated in 336 (54.5%), but performed in only 145 (43.2%). The need for CD screening was highest in luminal GI and inflammatory bowel disease clinics, followed by biliary and hepatology clinics (p<0.0001); CD screening rate was highest in the luminal GI clinic (p=0.002). Of 145 patients screened, 4 patients (2.4%) had serology consistent with CD, of which 2 were proven by duodenal biopsy. Using this proportion, an additional 5 patients might have been diagnosed in 191 untested patients with indications for CD screening. Conclusions More than 50% of patients in a tertiary GI clinic have indications for CD screening, but <50% of indicated cases are screened. Case-finding techniques therefore are suboptimal, constituting a gap in patient care and an important target for future quality improvement initiatives.

Mo1278 Review of Systems and Medication Allergies Predict Presence and Severity of Functional GI Disorders (FGIDs)

Background: IBS is a common functional GI syndrome with a prominent pain component. History of physical, sexual, and/or emotional abuse is more prevalent among IBS sufferers. Previously we reported that abuse is linked to more severe and frequent IBS symptoms and poorer health related quality of life (HRQOL). If abuse experiences heighten brain neurocircuitry sensitivity to pain experiences as has been suggested (Ringel Y et al Gastroenterol 2008), this study then sought to examine the effects of an abuse history on rates of functional GI disorder (FGID) diagnoses, non-GI diagnoses, and recent pain symptoms among an IBS population; further, we aimed to determine whether experiences of multiple forms of abuse resulted in greater likelihood of developing functional GI and non-GI complaints. Methods: Consecutive GI outpatients were invited to complete ROME III Research Diagnostic Questionnaire to establish FGID criteria. Self-report questionnaires on abuse history (Life-Stress Questionnaire) were obtained, with a focus on physical, sexual, and emotional abuse. IBS patients with histories of any form of these abuse experiences were defined as IBS+/Abuse+. Recent non-GI somatic symptoms (PHQ-12), and historical somatic pain diagnoses (e.g., fibromyalgia, headache, chronic back pain) were recorded. 272 ROMEdefined IBS subjects (50.1±0.9 yrs, 81% female) were identified, and reported greater rates of abuse compared to a non-IBS comparator group (n=246): physical (18.1% vs 6.6%), sexual (15.5% vs 7.4%), and emotional (31.7% vs 16.9%) (p 1 form of abuse. Compared to IBS subjects without abuse histories (IBS+/Abuse-), IBS+/Abuse+ subjects had greater total numbers of ROME diagnoses (2.5±0.3 vs 2.1±0.3, p=0.10), non-GI pain diagnoses (1.9±0.2 vs. 0.9±0.08, p<0.001), and more recent somatic symptoms (9.6±0.5 vs. 7.7±0.4, p=0.001). All forms of abuse experiences imposed similar risk of functional syndromes. An additive effect of multiple forms of abuse was observed, such that greater numbers non-GI pain disorders (F=13.5, p<0.001) and somatic symptom complaints (F=5.8, p=0.001) were noted with the experience of multiple forms of abuse. This additive effect was not relevant to the number of ROME diagnoses recorded, however (F=0.69, p=0.55). Conclusions: Abuse experiences common in IBS patients are associated with reports of greater non-GI symptoms, historical somatic diagnoses, and to a lesser extent additional FGID diagnoses in IBS patients; these relationships are particularly robust when multiple forms of abuse have been experienced. These observations provide indirect evidence of an enhanced susceptibility to both GI and somatic functional disorders following abuse.