Phenotypic shift of small intestinal intra-epithelial type 1 innate lymphoid cells in celiac disease is associated with enhanced cytotoxic potential.

The small intestinal (SI) epithelium harbors a heterogeneous population of lymphocytes that mediate mucosal damage and repair in celiac disease (CD). The composition and roles of human proximal SI intra-epithelial innate lymphoid cells (ILCs), and their alterations in CD, are not well understood. We report that duodenal intra-epithelial ILCs predominantly consist of natural killer (NK)p44+ CD127- cytotoxic ILC1s and NKp44- CD127+ helper ILC1s, while ILC3s only represent a minor population. In patients with newly diagnosed or active CD (ACD) and refractory CD type 1 (RCD I), the frequency of SI NKp44+ ILCs is decreased, with restoration of NKp44+ ILC frequency observed in patients adhering to a gluten-free diet who show evidence of mucosal healing. Moreover, the frequency of SI NKp44- ILCs is increased in ACD and RCD I patients and correlates with the severity of villous atrophy and epithelial damage, as assessed by serum levels of fatty acid binding protein 2 (FABP2). We show that the ILC alterations in CD represent a phenotypic shift of cytotoxic ILC1s rather than an increase in helper ILC1s or transdifferentiation of ILC1s to ILC3s, and activation-induced loss of NKp44 by cytotoxic ILC1s is associated with increased interferon (IFN)-γ expression and release of lytic granules. These findings suggest that intra-epithelial NKp44- CD127- cytotoxic ILC1s may contribute to mucosal damage in CD.

Portable gluten sensors: qualitative assessments by adults and adolescents with coeliac disease.

BACKGROUND: Portable gluten sensors are now commercially available to the public, although there is genuine uncertainty within the medical community over whether they should be used for coeliac disease management. The present study described qualitatively the experience of using a portable gluten sensor for 15 adults and 15 adolescents with coeliac disease participating in a 3-month pilot clinical trial. METHODS: Participants were 30 individuals, aged 13-70 years, with biopsy-confirmed coeliac disease on a gluten-free diet. All received a portable gluten sensor and were randomised to low, medium, and high numbers of single-use capsules. Open-ended questions addressed likes and dislikes using the portable gluten sensor after 3 months. Major themes were identified and described. RESULTS: Participants liked that the portable gluten sensor provided extra assurance to check foods presented as gluten-free, the convenient size and portability, the added sense of control, and overall peace-of-mind. Participants disliked having attention drawn to them when using the sensor and feeling as if they were deterring others from eating. Participants also disliked the physical difficulty associated with using the capsules, questionable accuracy and the inability to test fermented foods. Adults were more enthusiastic about the sensor than adolescents. CONCLUSIONS: Positive and negative experiences may be expected when using commercially available portable gluten sensors to help manage coeliac disease. As future versions of this and other gluten sensors become available, it will be important to investigate the relationship between users' experience with the sensors and long-term outcomes such as mucosal healing and quality of life.

Diminished quality of life among adolescents with coeliac disease using maladaptive eating behaviours to manage a gluten-free diet: a cross-sectional, mixed-methods study.

BACKGROUND: Certain approaches to managing a strict gluten-free diet (GFD) for coeliac disease (CD) may lead to impaired psychosocial well-being, a diminished quality of life (QOL) and disordered eating. The present study aimed to understand adolescents' approaches to managing a GFD and the association with QOL. METHODS: Thirty adolescents with CD (13-17 years old) following the GFD for at least 1 year completed the Celiac Dietary Adherence Test (CDAT) and QOL survey. Their approaches to GFD management were explored using a semi-structured interview, where key themes were developed using an iterative process, and further analysed using a psychosocial rubric to classify management strategies and QOL. CDAT ratings were compared across groups. RESULTS: Gluten-free diet management strategies were classified on a four-point scale. Adaptive eating behaviours were characterised by greater flexibility (versus rigidity), trust (versus avoidance), confidence (versus controlling behaviour) and awareness (versus preoccupation) with respect to maintaining a GFD. Approximately half the sample (53.3%) expressed more maladaptive approaches to maintaining a GFD and those who did so were older with lower CD-Specific Pediatric Quality of Life (CDPQOL) scores, mean subscale differences ranging from 15.0 points for Isolation (t = 2.4, P = 0.03, d.f. = 28) to 23.4 points for Limitations (t = 3.0, P = 0.01, d.f. = 28). CONCLUSIONS: Adolescents with CD who manage a GFD with maladaptive eating behaviours similar to known risk factors for feeding and eating disorders experience diminished QOL. In accordance with CD management recommendations, we recommend ongoing follow-up with gastroenterologists and dietitians and psychosocial support referrals, as needed.

Persistent mucosal damage and risk of epilepsy in people with celiac disease.

BACKGROUND AND PURPOSE: Celiac disease (CD) is associated with an increased risk of developing epilepsy, a risk that persists after CD diagnosis. A significant proportion of patients with CD have persistent villous atrophy (VA) on follow-up biopsy. The objective of this study was to determine whether persistent VA on follow-up biopsy affected long-term epilepsy risk and epilepsy-related hospital emergency admissions. METHODS: This was a nationwide cohort study. We identified all people in Sweden with histological evidence of CD who underwent a follow-up small intestinal biopsy (1969-2008). We compared those with persistent VA with those who showed histological improvement, assessing the development of epilepsy and related emergency hospital admissions (defined according to relevant International Classification of Diseases codes in the Swedish Patient Register). Cox regression analysis was used to assess outcome measures. RESULTS: Villous atrophy was present in 43% of 7590 people with CD who had a follow-up biopsy. The presence of persistent VA was significantly associated with a reduced risk of developing newly-diagnosed epilepsy (hazard ratio, 0.61; 95% confidence interval, 0.38-0.98). On stratified analysis, this effect was primarily amongst males (hazard ratio, 0.35; 95% confidence interval, 0.15-0.80). Among the 58 patients with CD with a prior diagnosis of epilepsy, those with persistent VA were less likely to visit an emergency department with epilepsy (hazard ratio, 0.37; 95% confidence interval, 0.09-1.09). CONCLUSIONS: In a population-based study of individuals with CD, persisting VA on follow-up biopsy was associated with reduced future risk of developing epilepsy but did not influence emergency epilepsy-related hospital admissions. The mechanism as to why persistent VA confers this benefit requires further exploration.

No association between biopsy-verified celiac disease and subsequent amyotrophic lateral sclerosis--a population-based cohort study.

BACKGROUND AND PURPOSE: Earlier data suggest an association between amyotrophic lateral sclerosis (ALS) and autoimmune disease, but data on its association with celiac disease (CD) are limited. METHODS: The risk of ALS in 29 093 individuals with CD, according to small intestine biopsy (villous atrophy, Marsh 3) carried out at Sweden's 28 pathology departments in 1969-2008, was compared with that in 144 515 age- and sex-matched reference individuals from the general population. ALS was defined as a hospitalization or outpatient visit with ALS according to the Swedish Patient Register. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for ALS. RESULTS: During follow-up 12 (3.7/100 000 person-years) individuals with CD and 56 (3.5/100 000 person-years) reference individuals had a diagnosis of ALS. This corresponded to an HR of 1.0 (95% CI 0.5-1.8). HRs were significantly higher in the first year of follow-up (4.1; 1.2-13.4) than 1-5 years after first CD diagnosis (0.8; 0.2-2.7) or after more than 5 years of follow-up (0.5; 0.2-1.5). Relative risk estimates were similar in men and women but were higher at the end of the study period [HR for ALS in patients diagnosed with CD in year 2000 or later was 2.1 (95% CI 0.9-4.8)]. CONCLUSIONS: This study found no association between CD and ALS. Earlier reports of a positive association may be due to surveillance bias just after CD diagnosis or expedited diagnostic work-up of ALS.

Systematic review with meta-analysis: the prevalence of coeliac disease in patients with osteoporosis.

BACKGROUND: Earlier studies have produced highly varying risk estimates for the prevalence of coeliac disease (CD) in osteoporosis. AIMS: To investigate the prevalence of CD among individuals with osteoporosis. METHODS: We conducted a systematic review of articles published in PubMed, Medline or EMBASE through May 2017 to identify studies looking at prevalence of CD in patients with osteoporosis. Search terms included "coeliac disease" combined with "fractures", "bone disease", "bone density", "densitometry", "osteoporos*", "osteomal*", "osteodys" or "dexa" or "dxa" or "skelet". Non-English papers with English-language abstracts were included. We used fixed-effects inverse variance-weighted models, and tested heterogeneity through subgroup analysis as well as through meta-regression. RESULTS: We identified eight relevant studies, comprising data from 3188 individuals with osteoporosis. Of these, 59 individuals (1.9%) had CD. A weighted pooled analysis demonstrated biopsy-confirmed CD in 1.6% (95% CI = 1.1%-2.0%) of individuals with osteoporosis. The heterogeneity was moderate (I2  = 40.1%), and influenced by the underlying CD prevalence in the general population. After adding four studies (n = 814) with CD defined as positive tissue transglutaminase or endomysial antibodies, the pooled prevalence was comparable (1.6%; 95% CI = 1.2%-2.0%). CONCLUSIONS: About 1 in 62 individuals with osteoporosis, or 1.6%, have biopsy-verified CD. This prevalence is comparable to that in the general population. These findings argue against routinely screening patients with osteoporosis for CD, which is contrary to current guideline recommendations. Additional studies are needed to determine the true utility of such screening programs.

Factors associated with villus atrophy in symptomatic coeliac disease patients on a gluten-free diet.

BACKGROUND: Duodenal injury persists in some coeliac disease patients despite gluten-free diet, and is associated with adverse outcomes. AIM: To determine the prevalence and clinical risk factors for persistent villus atrophy among symptomatic coeliac disease patients. METHODS: A nested cross-sectional analysis was performed on coeliac disease patients with self-reported moderate or severe symptoms while following a gluten-free diet, who underwent protocol-mandated duodenal biopsy upon enrolment in the CeliAction clinical trial. Demographic factors, symptom type, medication use, and serology were examined to determine predictors of persistent villus atrophy. RESULTS: Of 1345 symptomatic patients, 511 (38%, 95% CI, 35-41%) were found to have active coeliac disease with persistent villus atrophy, defined as average villus height to crypt depth ratio ≤2.0. On multivariable analysis, older age (OR, 5.1 for ≥70 vs. 18-29 years, 95% CI, 2.5-10.4) was a risk factor while longer duration on gluten-free diet was protective (OR, 0.37, 95% CI, 0.24-0.55 for 4-5.9 vs. 1-1.9 years). Villus atrophy was associated with use of proton-pump inhibitors (PPIs; OR, 1.6, 95% CI, 1.1-2.3), non-steroidal anti-inflammatory drugs (NSAIDs; OR, 1.64, 95% CI, 1.2-2.2), and selective serotonin reuptake inhibitors (SSRIs; OR, 1.74, 95% CI, 1.2-2.5). Symptoms were not associated with villus atrophy after adjusting for covariates. Conclusions A majority of symptomatic coeliac disease patients did not have active disease on follow-up histology. Symptoms were poorly predictive of persistent mucosal injury. The impact of NSAIDs, PPIs, and SSRIs on mucosal healing in coeliac disease warrants further study.

The coeliac stomach: gastritis in patients with coeliac disease.

BACKGROUND: Lymphocytic gastritis (LG) is an uncommon entity with varying symptoms and endoscopic appearances. This condition, as well as two forms of H. pylori-negative gastritis [chronic active gastritis (CAG) and chronic inactive gastritis (CIG)], appears to be more common in patients with coeliac disease (CD) based on single-centred studies. AIM: To compare the prevalence of LG, CAG and CIG among those with normal duodenal histology (or nonspecific duodenitis) and those with CD, as defined by villous atrophy (Marsh 3). METHODS: We analysed all concurrent gastric and duodenal biopsy specimens submitted to a national pathology laboratory during a 6-year period. We performed multiple logistic regression to identify independent predictors of each gastritis subtype. RESULTS: Among patients who underwent concurrent gastric and duodenal biopsy (n = 287,503), the mean age was 52 and the majority (67%) were female. Compared to patients with normal duodenal histology, LG was more common in partial villous atrophy (OR: 37.66; 95% CI: 30.16-47.03), and subtotal/total villous atrophy (OR: 78.57; 95% CI: 65.37-94.44). CD was also more common in CAG (OR for partial villous atrophy 1.93; 95% CI: 1.49-2.51, OR for subtotal/total villous atrophy 2.42; 95% CI: 1.90-3.09) and was similarly associated with CIG (OR for partial villous atrophy 2.04; 95% CI: 1.76-2.35, OR for subtotal/total villous atrophy 2.96; 95% CI: 2.60-3.38). CONCLUSIONS: Lymphocytic gastritis is strongly associated with coeliac disease, with increasing prevalence correlating with more advanced villous atrophy. Chronic active gastritis and chronic inactive gastritis are also significantly associated with coeliac disease. Future research should measure the natural history of these conditions after treatment with a gluten-free diet.

Predictors of persistent villous atrophy in coeliac disease: a population-based study.

BACKGROUND: Villous atrophy (VA) with intraepithelial lymphocytosis is the histological hallmark of coeliac disease (CD), but reported rates of mucosal recovery are variable. AIM: To determine the impact of age and other demographic variables on the probability of persistent VA on follow-up biopsy. METHODS: We identified patients with VA on duodenal histology at all 28 Swedish pathology departments during the years spanning 1969-2008. We examined age, gender, calendar period, duration of disease and educational attainment to determine predictors of persistent VA. RESULTS: Of 7648 patients with CD who underwent follow-up biopsy, persistent VA was present in 3317 (43%; 95% CI 42-44%). The effect of age on persistent VA varied according to time period; among those biopsied in the years spanning 2000-2008, the prevalence of persistent VA was 31%, and increasing age was associated with increasing rates of persistent VA (17% among those younger than 2 years compared to 56% among those ≥70 years). In contrast, persistent VA did not vary widely by age in earlier years. On multivariate analysis (restricted to the calendar period 2000-2008, 2-5 years after CD diagnosis), persistent VA was more common among males (OR 1.43; 95% CI 1.07-1.90) and less common among patients with higher educational attainment (OR for college degree vs. <2 years of high school 0.52, 95% CI 0.35-0.78). CONCLUSIONS: The prevalence of persistent villous atrophy has changed over time, with greater rates of healing in recent years. Social differences in persistent villous atrophy suggest that access and/or education regarding the gluten-free diet impact mucosal healing.

Development and validation of a clinical prediction score (the SCOPE score) to predict sedation outcomes in patients undergoing endoscopic procedures.

BACKGROUND: Use of anaesthesia services during endoscopy has increased, increasing cost of endoscopy. AIM: To identify risk factors for and develop a clinical prediction score to predict difficult conscious sedation. METHODS: We performed a retrospective cross-sectional study of all patients who underwent oesophagogastroduodenoscopy (OGD) and colonoscopy with endoscopist-administered conscious sedation. The endpoint of difficult sedation was a composite of receipt of high doses (top quintile) of benzodiazepines and opioids, or the documentation of agitation or discomfort. Univariate and multivariate analyses were performed to measure association of the outcome with: age, sex, body mass index (BMI), procedure indication, tobacco use, self-reported psychiatric history, chronic use of benzodiazepines, opioids or other psychoactive medications, admission status and participation of a trainee. A clinical prediction score was constructed using statistically significant variables. RESULTS: We identified 13,711 OGDs and 21,763 colonoscopies, 1704 (12.4%) and 2299 (10.6%) of which met the primary endpoint, respectively. On multivariate analysis, factors associated with difficulty during OGD were younger age, procedure indication, male sex, presence of a trainee, psychiatric history and benzodiazepine and opioid use. Factors associated with difficulty during colonoscopy were younger age, female sex, BMI <25, procedure indication, tobacco, benzodiazepine, opioid and other psychoactive medication use. A clinical prediction score was developed and validated that may be used to risk-stratify patients undergoing OGD and colonoscopy across five risk classes. CONCLUSIONS: Using the Stratifying Clinical Outcomes Prior to Endoscopy (SCOPE) score, patients may be risk stratified for difficult sedation/high sedation requirement during OGD and colonoscopy.

Mucosal healing and mortality in coeliac disease.

BACKGROUND: Coeliac disease (CD), characterised by the presence of villous atrophy (VA) in the small intestine, is associated with increased mortality, but it is unknown if mortality is influenced by mucosal recovery. AIMS: To determine whether persistent VA is associated with mortality in CD. METHODS: Through biopsy reports from all pathology departments (n = 28) in Sweden, we identified 7648 individuals with CD (defined as VA) who had undergone a follow-up biopsy within 5 years following diagnosis. We used Cox regression to examine mortality according to follow-up biopsy. RESULTS: The mean age of CD diagnosis was 28.4; 63% were female; and the median follow-up after diagnosis was 11.5 years. The overall mortality rate of patients who underwent follow-up biopsy was lower than that of those who did not undergo follow-up biopsy (Hazard Ratio 0.88, 95% CI: 0.80-0.96). Of the 7648 patients who underwent follow-up biopsy, persistent VA was present in 3317 (43%). There were 606 (8%) deaths. Patients with persistent VA were not at increased risk of death compared with those with mucosal healing (HR: 1.01; 95% CI: 0.86-1.19). Mortality was not increased in children with persistent VA (HR: 1.09 95% CI: 0.37-3.16) or adults (HR 1.00 95% CI: 0.85-1.18), including adults older than age 50 years (HR: 0.96 95% CI: 0.80-1.14). CONCLUSIONS: Persistent villous atrophy is not associated with increased mortality in coeliac disease. While a follow-up biopsy will allow detection of refractory disease in symptomatic patients, in the select population of patients who undergo repeat biopsy, persistent villous atrophy is not useful in predicting future mortality.

Risk of colorectal adenomas and advanced neoplasia in Hispanic, black and white patients undergoing screening colonoscopy.

BACKGROUND: Racial and ethnic differences in the risk of premalignant colorectal neoplasia have not been extensively studied. AIM: To measure adenoma prevalence among asymptomatic white, black and Hispanic patients undergoing screening colonoscopy. METHODS: In this cross sectional cohort study, data from individuals ≥50 years undergoing first-time colonoscopy since 2006 at a single tertiary-care medical centre were obtained from the electronic medical record. Adenoma prevalence among whites, blacks and Hispanics was calculated; multivariate Poisson and logistic regression were used to identify factors independently associated with adenoma rates and the presence of advanced adenomas. RESULTS: We identified 5075 eligible subjects: 3542 (70%) whites, 942 (18%) Hispanics and 591 (12%) blacks. The mean age was 62.2 years with 58% women. At least one adenoma was detected in 19%, 22% and 26% of whites, Hispanics and blacks respectively (Hispanics vs. whites P = 0.09; blacks vs. whites P = 0.0001). Isolated proximal adenomas were present in 9% of whites, 11% of Hispanics (P = 0.03) and 11% of blacks (P = 0.03). In multivariate analyses, a higher rate of adenomas was present in Hispanics (RR: 1.37, 95% CI: 1.20-1.57) and blacks (RR: 1.76, 95% CI: 1.52-2.04) than whites. Hispanics and blacks also had an increased risk of advanced adenomas compared to whites (OR(Hispanics) : 2.25, 95% CI: 1.62-3.11; OR(blacks) : 1.91, 95% CI: 1.27-2.86). CONCLUSIONS: Adenoma prevalence was higher in blacks and Hispanics than in whites. Both groups were at greater risk of having proximal adenomas in the absence of any distal pathology than whites, where these lesions would have only been detected by colonoscopy. Efforts to promote screening are necessary among diverse, under-represented populations.

Risk of colorectal adenomas in patients with coeliac disease.

BACKGROUND: Coeliac disease is associated with an increased risk of lymphoma and small bowel malignancy, but most studies have found no increased risk of colorectal cancer. AIM: To compare the prevalence of colorectal adenomas in coeliac disease patients with that in non-coeliac disease controls. METHODS: We identified all coeliac disease patients who underwent colonoscopy at our institution during a 44-month period. We matched each patient with non-coeliac disease controls by age, gender and endoscopist. We compared the adenoma prevalence between these groups, and used multivariate analysis to assess the independent association of coeliac disease with adenomas. RESULTS: We identified 180 patients with coeliac disease and 346 controls. At least one adenoma was present in 13% of coeliac disease patients and 17% of controls (P = 0.20). On multivariate analysis, age (OR per year 1.04, 95% CI 1.02-1.07) and male gender (OR 2.33, 95% CI 1.36-3.98) were associated with adenomas, while the relationship between coeliac disease and adenomas remained null (OR 0.75, 95% CI 0.41-1.34). CONCLUSIONS: Coeliac disease is not associated with an increased risk of colorectal neoplasia. The lack of increased risk of colorectal cancer observed in population studies is related to a true average risk of colorectal neoplasia, rather than artifactually reflecting increased colonoscopy and associated polypectomies in the coeliac population.