Clinical Presentation and Spectrum of Gluten Symptomatology in Celiac Disease.

Views on the clinical presentation and symptomatology of celiac disease have evolved alongside advances in disease detection and understanding of disease pathogenesis. Although historically regarded as a pediatric illness characterized by malabsorption, it is now better viewed as an immune illness of gluten-specific T cells with systemic manifestations affecting all ages. Its broad presentation, including frequent extraintestinal manifestations and asymptomatic disease, contributes to suboptimal disease detection. Adverse symptoms greatly impact patient quality of life and can result from chronic gluten exposure in untreated disease or those poorly responsive to the gluten-free diet. They can also present as acute symptoms after episodic gluten exposure. Functional gastrointestinal disease is a common comorbidity. Biomarkers like interleukin-2 that are highly sensitive and specific for celiac disease highlight a role for gluten-specific T cells in acute gluten symptomatology. A mechanistic understanding of symptoms will inform approaches to better measure and treat them effectively.

Phase I double-blind, placebo-controlled trial of dolcanatide (SP-333) 27 mg to explore colorectal bioactivity in healthy volunteers.

Guanylyl cyclase C (GUCY2C) is a tumor-suppressing receptor silenced by loss of expression of the luminocrine hormones guanylin and uroguanylin early in colorectal carcinogenesis. This observation suggests oral replacement with a GUCY2C agonist may be an effective targeted chemoprevention agent. Previous studies revealed that linaclotide, an oral GUCY2C agonist formulated for gastric release, did not persist to activate guanylyl cyclase signaling in the distal rectum. Dolcanatide is an investigational oral uroguanylin analog, substituted with select D amino acids, for enhanced stability and extended persistence to activate GUCY2C in small and large intestine. However, the ability of oral dolcanatide to induce a pharmacodynamic (PD) response by activating GUCY2C in epithelial cells of the colorectum in humans remains undefined. Here, we demonstrate that administration of oral dolcanatide 27 mg daily for 7 d to healthy volunteers did not activate GUCY2C, quantified as accumulation of its product cyclic GMP, in epithelial cells of the distal rectum. These data reveal that the enhanced stability of dolcanatide, with persistence along the rostral-caudal axis of the small and large intestine, is inadequate to regulate GUCY2C across the colorectum to prevent tumorigenesis. These results highlight the importance of developing a GUCY2C agonist for cancer prevention formulated for release and activity targeted to the colorectum.

Symptoms of gluten ingestion in patients with non-celiac gluten sensitivity: A randomized clinical trial.

OBJECTIVES: Non-celiac gluten sensitivity (NCGS) is the presence of symptoms induced by gluten and relieved by a gluten-free diet (GFD) in patients without celiac disease or wheat allergy. Studies are mixed as to whether gluten is the main symptom trigger in patients with NCGS. Gluten immunogenic peptides (GIPs) in stool and urine are novel methods to monitor GFD compliance. Few studies have investigated their use in patients with NCGS. The aim of this study was to assess whether patients with NCGS have increased symptoms with gluten ingestion and to assess compliance with the GFD using stool and urine GIPs. METHOD: This was a prospective, randomized, double-blinded crossover trial evaluating symptoms in patients with NCGS. Thirty patients with NCGS and 43 healthy controls were placed on a GFD. Patients received 0.5 or 2 g/d of gluten for 7 d each. The remaining weeks, they received placebo for a total of 4 wk. Symptoms were evaluated weekly using the Celiac Symptom Index (CSI). Urine and stool samples were collected weekly and measured for the detection of GIPs to detect exposure to gluten. RESULTS: There was no difference in symptom severity within the NCGS group whether receiving placebo or gluten (32.69 versus 31.54, P = 0.64). Patients with NCGS had significantly higher CSI scores at baseline than healthy controls. Patients with NCGS were less likely to have stool and urine GIPs than healthy patients. CONCLUSION: Patients with NCGS were more adherent to the GFD based on stool and urine GIP results. Patients with NCGS had increased symptom severity at baseline compared with healthy controls. Neither group had significantly increased symptoms after ingestion of gluten.

The impact of risk factors on gastroparesis at an urban medical center.

BACKGROUND: Gastroparesis is a complex and poorly understood disease. The literature is lacking with respect to the epidemiology of patient comorbidities and their effect on gastric emptying. We aimed to describe the most common comorbid conditions among patients with gastroparesis in an urban population and quantify the effect of these comorbidities on the severity of delayed gastric emptying (DGE). METHODS: We examined the medical records of all patients diagnosed with gastroparesis at a quaternary care center between 2014 and 2015. The severity of DGE was analyzed after patients were stratified for possible causative etiologies. Likelihood ratio tests were used to assess the significance of demographic and scintigraphic variation in this population. RESULTS: Of the 221 patients, 56.1% were Caucasian and 31.7% were African American. Among these patients, 29.4% had evidence of medication-associated gastroparesis, 29.0% had diabetes-associated gastroparesis, and 31.7% had idiopathic disease. African American patients with gastroparesis were more likely to have diabetic gastroparesis than patients of other races (P=0.01). There was a statistically significant relationship between the number of major risk factors and the severity of a patient's DGE (P=0.004). CONCLUSIONS: Among a diverse urban population, patients with DGE often carry multiple comorbid conditions that serve as risk factors for the development of gastroparesis, including prescriptions for narcotic medications. Greater numbers of these comorbid conditions are associated with more severe disease. Demographics are significantly associated with the etiology and severity of gastroparesis; in particular, African American patients are more likely to have diabetic gastroparesis than patients of other races.

Polyp Detection Rates among Body Mass Index Categories at First Screening Colonoscopy.

In the United States, obesity is an epidemic and colorectal cancer is the second deadliest cancer for men and women. A link between obesity and colorectal adenomas and carcinoma has been suggested but not proven. We sought out to determine if obesity was associated with increased rates of polyp formation. All patients undergoing a first screening colonoscopy by one of the participating endoscopists at Thomas Jefferson University Hospital from January 2012 to March 2015 were considered for the study. Their demographics, body mass index (BMI), and colonoscopy findings were recorded at the time of the procedure and prospectively maintained in our database. The final pathologic diagnosis was recorded for each participant as it became available. A total of 758 subjects were included. Of these, 22 per cent had a BMI <25 kg/m2, 29 per cent had a BMI between 25 and 29.9 kg/m2, and 49 per cent had a BMI of at least 30 kg/m2. Overall, 21.9 per cent of the participants were found to have at least one adenomatous polyp. The polyp detection rates were 24.4 per cent in the group with a BMI less than 25, 20.5 per cent in the overweight group, and 21.6 per cent in the obese group. Our study included 56 super obese individuals with a BMI ≥45 kg/m2. About 17.9 per cent of subjects in the super obese group had an adenomatous polyp. There were no differences in the incidence of adenomatous polyps between BMI categories in our study.

Survey of anal sphincter dysfunction using anal manometry in patients with fecal incontinence: a possible guide to therapy.

BACKGROUND: Despite the surge of new medical and surgical approaches to treat fecal incontinence, the types of sphincter abnormalities in patients with incontinence have not been well characterized. We aimed to categorize anal sphincter dysfunction using anorectal manometry in patients with fecal incontinence as a potential guide for improved treatment. METHODS: A retrospective review of 162 consecutive patients with fecal incontinence referred for anorectal manometry was performed. Resting anal pressure and maximal squeeze pressure were considered as measures of internal anal sphincter and external anal sphincter function respectively. RESULTS: Mean age of the patients was 63 years (13-89); females (81.5%) and males (18.5%). 74% of the patients had sphincter dysfunction on anorectal manometry. Internal anal sphincter dysfunction was present in 62% patients vs. external anal sphincter dysfunction present in 44% patients. 80% females had abnormal manometry vs. 44% in males (P<0.0001). Internal anal sphincter dysfunction was present in 68% females vs. 37% in males (P=0.0026). CONCLUSIONS: Overall, abnormal anorectal manometry studies revealed that internal anal sphincter dysfunction is the most common finding, alone or in combination with external anal sphincter dysfunction. We suggest that anorectal manometry may be important to delineate anal sphincter function prior to using newer therapeutic mechanical devices. Future studies using pharmacological agents to increase internal anal sphincter tone may be of clinical importance. Finally, the classification of fecal incontinence based on the type of sphincter dysfunction may be an improved guide in the selection of newer agents in treating fecal incontinence.

Increased rates of pregnancy complications in women with celiac disease.

BACKGROUND: Celiac disease is an immune-mediated small bowel disorder that develops in genetically susceptible individuals upon exposure to dietary gluten. Celiac disease could have extra-intestinal manifestations that affect women's reproductive health. The aim of this study was to investigate fertility and outcomes of pregnancy among women with celiac disease. METHODS: In a retrospective cohort study, we analyzed information collected from patients at a tertiary care celiac center and from members of 2 national celiac disease awareness organizations. Women without celiac disease were used as controls. Women completed an anonymous online survey, answering 43 questions about menstrual history, fertility, and outcomes of pregnancy (329 with small bowel biopsy-confirmed celiac disease and 641 controls). RESULTS: Of the 970 women included in the study, 733 (75.6%) reported that they had been pregnant at some point; there was no significant difference between women with celiac disease (n=245/329, 74.5%) and controls (488/641, 76.1%; P=0.57). However, fewer women with celiac disease than controls (79.6% vs. 84.8%) gave birth following 1 or more pregnancies (P=0.03). Women with celiac disease had higher percentages of spontaneous abortion than controls (50.6% vs. 40.6%; P=0.01), and of premature delivery (23.6% vs. 15.9% among controls; P=0.02). The mean age at menarche was higher in the celiac disease group (12.7 years) than controls (12.4 years; P=0.01). CONCLUSIONS: In a retrospective cohort analysis examining reproductive features of women with celiac disease, we associated celiac disease with significant increases in spontaneous abortion, premature delivery, and later age of menarche.

Physicians Caring for Celiac Patients do not Routinely Recommend Screening of First-Degree Family Members.

AIM: Screening first-degree relatives of celiac disease (CD) patients offers an opportunity to diagnose CD in a high-risk population.This study aims to determine how frequently CD patients receive a physician-issued recommendation for first-degree relative screening. MATERIALS AND METHODS: A 12-question survey assessing whether CD patients receive a physician recommendation to screen first-degree relatives for CD, and the impact of such a recommendation, was validated with outpatients in a university gastroenterology practice ("University"). The 12-question survey was then distributed online to members of a celiac organization - the National Foundation for Celiac Awareness ("NFCA"). Results were collected over 3 months. Univariate analysis was used to compare cohort means and assess the association between demographic and diagnostic factors and first-degree relative screening recommendations. RESULTS: 87 University patients participated in the validation phase. Test-retest reliability of 4 key survey questions was high (Kappa coefficient > 0.80). The main analyses were based on data from 677 NFCA and 82 University respondents. Respondents were predominantly female, with a mean age of 45 years. Significantly more University patients received a recommendation for screening (78% vs 44%, p < 0.001). Ninety-eight percent receiving a screening recommendation (both groups) discussed this with family members, leading to CD screening (University 71%, NFCA 79%) and, ultimately, a CD diagnosis (University 18%, NFCA 27%). CONCLUSIONS: Physicians of CD patients often do not recommend screening first-degree family members. The high clinical impact of this recommendation suggests that greater physician compliance with screening may increase the diagnosis of CD in high risk individuals.

Physicians-in-training attitudes on patient safety: 2003 to 2008.

OBJECTIVE: : Physician trainees will embody medicine's future culture. We assess whether trainees' patient safety attitudes have evolved over time. METHODS: : We anonymously surveyed more than 800 house staff and fourth-year medical students (MS 4) in 2008, at 1 academic institution, with a 19-item questionnaire and compared their responses to the 2003 responses at the same institution on the same questionnaire. RESULTS: : A total of 463 trainees (53%) completed the 2008 survey, with a mean overall safety score of 3.54, which significantly improved from the 2003 overall score of 3.41 (P < 0.001). Compared with those from 2003, respondents in 2008 more strongly agree that physician-nurse teamwork (P = 0.001), attending supervision (P = 0.017), 80-hour workweek (P < 0.001), computer order entry (P < 0.001), and improved resident sign-out (P < 0.001) help reduce adverse events. The 2008 trainees feel more prepared to prevent adverse events (P = 0.030) and more acknowledge the ethical responsibility to disclose adverse events to patients (P = 0.002). However, compared with 2003, fewer 2008 respondents felt that reducing nurses' patient load would reduce adverse events (P = 0.015); on 8 questionnaire items, there were no significant attitudinal changes between 2003 and 2008. CONCLUSIONS: : Physician trainee safety attitudes at 1 institution improved between 2003 and 2008, and these trainees support many system-based solutions to adverse events. The changes seem incremental and responses do not fully align with all aspects of a safety culture. Cultural change in health care must involve trainees and address their attitudes.

Special considerations for women with IBD.

Inflammatory bowel diseases (IBD), namely Crohn disease (CD) and ulcerative colitis (UC), are common in Western society. Because at least half of the patients suffering from these diseases are women, it is important that physicians are aware of their gender-specific needs. There are multiple important concerns for women with UC and CD including issues of body image and sexuality, menstruation, contraception, screening for cervical cancer, matters related to menopause and hormone replacement therapy, osteoporosis, and the overlap seen between IBS and IBD. In this article, we have addressed these important, non-pregnancy-related issues faced by women with IBD.

Utilization of the office, hospital and emergency department for adult sickle cell patients: a five-year study.

Sickle cell disease (SCD) is a hematological disorder that is manifested primarily by severe pain and chronic organ damage. Little normative data exists on what the usual healthcare utilization is of a population of SCD patients, especially adults. Our study analyzed the office, emergency department (ED) and hospital use data for 142 patients who received care for three consecutive years. Relationships between health service use, patient age, gender and sickle cell phenotype were described. Multivariate analyses studied relationships between demographic and clinical characteristics and levels of office, independent ED and inpatient encounters over a five-year period (1997-2001). We found female patients were older and had less ED and hospital admissions. The 20% highest inpatient utilizers accounted for 54% of the ED total visits, 52% of the ED independent visits, 54% of hospital bed days and 24% of office visits. The ED was a common place for utilization, with a mean of 7.4 visits per patient year, a third of which resulted in a hospital admission. The healthcare utilization of our adult sickle cell population is very complex, with a subset of our patients accounting for a majority of the resources used and female patients living longer but with less ED and hospital admissions.