Gluten-related Disorders From Bench to Bedside.

Celiac disease, non-celiac gluten sensitivity, and wheat allergy comprise 3 of the main conditions with wheat- and gluten-containing foods as the symptom trigger. Distinguishing between these entities can be daunting. In this review, we compare and contrast celiac disease, non-celiac gluten sensitivity, and wheat allergy to allow clinicians to determine which diagnosis fits their patient to facilitate high-quality management and longitudinal care.

Relationship between gluten availability and celiac disease prevalence: A geo-epidemiologic systematic review.

Celiac disease is a global disease requiring genetic susceptibility and gluten exposure to trigger immune-mediated enteropathy. The effect of the degree of gluten-containing grain availability on celiac disease prevalence is unknown. Our objective was to compare country-based gluten availability to celiac prevalence using a systematic literature review. We searched MEDLINE, Embase, Cochrane, and Scopus until May 2021. We included population-based serum screening with confirmatory testing (second serological study or small intestine biopsy) and excluded specific, high-risk, or referral populations. We determined country-specific gluten availability using the United Nations food balance for wheat, barley, and rye. Human leukocyte antigen (HLA) frequencies were obtained from allelefrequencies.net. The primary outcome was association between gluten-containing grain availability and celiac disease prevalence. Generalized linear mixed models method with Poisson's link was used for analysis. We identified 5641 articles and included 120 studies on 427 146 subjects from 41 countries. Celiac disease prevalence was 0-3.1%, median 0.75% (interquartile range 0.35, 1.22). Median wheat supply was 246 g/capita/day (interquartile range 214.8, 360.7). The risk ratio (RR) for wheat availability on celiac disease was 1.002 (95% confidence interval [CI]: 1.0001, 1.004, P = 0.036). A protective association was seen with barley, RR 0.973 (95% CI: 0.956, 0.99, P = 0.003), and rye, RR 0.989 (95% CI: 0.982, 0.997, P = 0.006). The RR for gross domestic product on celiac disease prevalence was 1.009 (95% CI: 1.005, 1.014, P < 0.001). The RR for HLA-DQ2 was 0.982 (95% CI: 0.979, 0.986, P < 0.001), and that for HLA-DQ8 was 0.957 (95% CI: 0.950, 0.964, P < 0.001). In this geo-epidemiologic study, gluten-containing grain availability showed mixed associations with celiac disease prevalence.

Self-Reported Gluten Intolerance Is Prevalent, but Not All Gluten-Containing Foods Are Equal.

BACKGROUND: Celiac disease prevalence approaches 1%; more suffer from non-celiac gluten sensitivity. AIMS: Our goal was to estimate the prevalence of gluten intolerance. METHODS: We invited US adults (18-80 years) via Amazon's mechanical Turk to complete an online survey. Gluten intolerance was defined as self-reported intolerance to wheat, barley, rye, flour, or pasta. Those with celiac disease were not excluded. RESULTS: We collected 2133 responses. Rate of gluten intolerance was 5.1% (95% CI 4.2-6.1%). Each food had different rates: wheat 4.8%, flour 1.2%, pasta 0.9%, barley 0.8%, and rye 0.8%. Among 108 adults reporting any gluten intolerance, 62.0% selected only wheat, 10.2% selected all gluten-containing grains excluding pasta and flour, and 5.6% selected all gluten-containing products. Overall intolerance to any food was 24.8% (95% CI 23.0-26.6%). Wheat was second only to lactose. CONCLUSIONS: Self-reported intolerance to wheat, but not all gluten-containing foods, is common. Findings may suggest poor knowledge of gluten-containing foods or that self-perceived non-celiac gluten sensitivity is prevalent.

Clinical Presentation of Small Intestinal Bacterial Overgrowth from Aerodigestive Tract Bacteria Versus Colonic-Type Bacteria: A Comparison Study.

BACKGROUND: Small Intestinal Bacterial Overgrowth (SIBO) is a heterogenous syndrome from excessive bacteria in the small intestine lumen. It is unknown if differences in type of bacterial overgrowth lead to differences in symptoms. METHODS: Patients with suspected SIBO were recruited prospectively. Exclusion criteria were probiotics, antibiotics, or bowel prep in preceding 30 days. Clinical characteristics, risk factors, and labs were collected. Proximal jejunal aspiration via upper enteroscopy was performed. Aerodigestive tract (ADT) SIBO was defined as > 105 CFU/mL of oropharyngeal and respiratory bacteria. Colonic-type SIBO was defined as > 104 CFU/mL of distal small bowel and colon bacteria. Aims were to compare symptom profiles, clinical complications, labs, and underlying risk factors between ADT and colonic-type SIBO. KEY RESULTS: We consented 166 subjects. Aspiration was not obtained in 22 and SIBO was found in 69 (49%) of 144 subjects. Daily abdominal distention trended towards more prevalent in ADT SIBO versus colonic-type SIBO (65.2% vs 39.1%, p = 0.09). Patient symptom scores were similar. Iron deficiency was more prevalent in ADT SIBO (33.3% vs 10.3%, p = 0.04). Subjects with colonic-type SIBO were more likely to have a risk factor for colonic bacteria colonization (60.9% vs 17.4%, p = 0.0006). Subjects with ADT SIBO were more likely to have a risk factor for diminished gastric acid (91.3% vs 67.4%, p = 0.02). CONCLUSIONS & INFERENCES: We found differences in iron deficiency and underlying risk factors between ADT and colonic-type SIBO. However, distinct clinical profiles remained elusive. Future research is needed to develop validated symptom assessment tools and distinguish cause from correlation.

Associations of Food Intolerance with Irritable Bowel Syndrome, Psychological Symptoms, and Quality of Life.

BACKGROUND & AIMS: The impact of different types of food intolerance on gastrointestinal symptoms and quality of life (QOL) is poorly understood. We aimed to investigate associations of food intolerance and type of intolerance with irritable bowel syndrome (IBS), health-related QOL, and psychological symptoms. METHODS: We conducted an observational study of United States-based adults through an online survey. Demographics, culprit foods, symptoms, medical evaluation, Rome IV criteria for IBS, health-related QOL (Short-Form Health Survey 12), and anxiety and depression scores (Hospital Anxiety and Depression Scale) were collected in participants with self-reported food intolerance (lactose, non-lactose food, lactose plus food intolerance), and controls with no intolerance. Univariable associations of group with study endpoints were analyzed with the Kruskal-Wallis and Pearson χ2 or Fisher exact test. Multivariable comparisons were analyzed by logistic and linear regression. RESULTS: A total of 197 patients with (59 lactose, 61 non-lactose food, 77 lactose plus food intolerance) and 273 patients without intolerance participated. Lactose, wheat, and eggs were the most common food triggers. Gas (54.2%), abdominal pain (40.2%), and diarrhea (37.3%) were frequently reported symptoms of food intolerance. Reactions caused 57.8% to eliminate the food. Rates of IBS, abnormal anxiety scores, and abnormal depression scores were highest in lactose plus food intolerance; Short-Form Health Survey 12 scores were lowest in lactose plus food intolerance. Multivariable analyses revealed all intolerance subgroups were more likely to have IBS than controls. CONCLUSIONS: Food intolerance is associated with IBS, anxiety, depression, and decreased health-related QOL and frequently leads to food elimination. Adults with lactose and lactose plus food intolerance have higher rates of IBS, increased psychological symptoms, and poorer QOL.

Latitude and Celiac Disease Prevalence: A Meta-Analysis and Meta-Regression.

BACKGROUND & AIMS: The latitudinal gradient effect is described for several autoimmune diseases including celiac disease in the United States. However, the association between latitude and global celiac disease prevalence is unknown. We aimed to explore the association between latitude and serology-based celiac disease prevalence through meta-analysis. METHODS: We searched MEDLINE, Embase, Cochrane, and Scopus databases from their beginning through June 29, 2018, to identify screening studies that targeted a general population sample, used serology-based screening tests, and provided a clear location from which we could assign a latitude. Studies were excluded if sampling was based on symptoms, risk factors, or referral. Study selection and data extraction were performed by independent reviewers. The association measures between latitude and prevalence of serology-based celiac disease were evaluated with random-effects meta-analyses and meta-regression. RESULTS: Of the identified 4667 unique citations, 128 studies were included, with 155 prevalence estimates representing 40 countries. Celiac disease was more prevalent at the higher latitudes of 51° to 60° (relative risk [RR], 1.62; 95% CI, 1.09-2.38) and 61° to 70° (RR, 2.30; 95% CI, 1.36-3.89) compared with the 41° to 50° reference level. No statistically significant difference was observed at lower latitudes. When latitude was treated as continuous, we found a statistically significant association between CD prevalence and latitude overall in the world (RR, 1.03, 95% CI, 1.01-1.05) and a subregional analysis of Europe (RR, 1.05; 95% CI, 1.02-1.07) and North America (RR, 1.1; 95% CI, 1.0-1.2). CONCLUSIONS: In this comprehensive review of screening studies, we found that a higher latitude was associated with greater serology-based celiac disease prevalence.

Relationships of Intestinal Lactase and the Small Intestinal Microbiome with Symptoms of Lactose Intolerance and Intake in Adults.

BACKGROUND: Approximately two-thirds of adults are genetically predisposed to decreased lactase activity after weaning, putting them at risk of lactose intolerance. However, symptoms are a poor marker of lactose maldigestion. AIMS: We assessed association between self-reported lactose intolerance and intestinal lactase, lactose intake, and the small intestinal microbiome. METHODS: Patients 18-75 years presenting for upper endoscopy were recruited prospectively. Observational study participants completed a lactose intolerance symptom questionnaire and reported lactose intake. Post-bulbar biopsies were obtained to measure lactase activity and assess the small intestinal mucosal microbiome. We compared intestinal lactase between patients with and without lactose intolerance. We assessed associations between lactose intolerance symptoms and lactase and lactose intake. We examined associations of small bowel microbial composition with self-reported lactose intolerance and symptoms. RESULTS: Among 34 patients, 23 (68%) reported lactose intolerance. Those with lactose intolerance had higher total symptom scores, more frequent bowel urgency, and more bowel movements after consuming dairy. The proportion of individuals with abnormal lactase activity did not differ by lactose intolerance status. Median lactase levels were correlated with total lactose intolerance symptom scores (p = 0.038) and frequency of bowel urgency (p = 0.012). Daily lactose intake did not differ between groups. In 19 patients, we observed significant associations of small intestinal microbiome beta diversity with stool consistency after consuming dairy (p = 0.03). CONCLUSIONS: Intestinal lactase is associated with lactose intolerance symptoms and bowel urgency in adults but does not distinguish the clinical phenotype entirely. Studying other contributing factors (microbiota, diet) may further clarify the pathophysiology of lactose intolerance.

Small Intestine Varices in Cirrhosis at a High-Volume Liver Transplant Center: A Retrospective Database Study and Literature Review.

INTRODUCTION: Esophageal varices are a well-characterized sequela of portal hypertension; however, less is known about varices arising in ectopic locations. We aimed to describe bleeding small intestine varices (SIV) in patients with cirrhosis and compare characteristics and outcomes to published case reports. METHODS: We performed an institutional chart review using billing codes and natural language processing between 2008 and 2019. Inclusion criteria were adult patients with cirrhosis and SIV verified by endoscopy, video capsule, or imaging. Patients with noncirrhotic portal hypertension and stomal varices were excluded. We examined demographic and clinical factors, characteristics of SIV, bleeding, intervention, and outcomes in our series and collated data from published cases identified during a literature review. RESULTS: We identified 71 patients with cirrhosis and SIV (18 bled). The literature search yielded 76 cases with bleeding SIV. Our series and published cases were matched for age, sex, liver disease etiology, and SIV location. Length of stay and transfusion requirements were similar. Aggregate initial treatments (number, hemostasis rate) included medical (n = 7, 57%), endoscopic (n = 48, 56%), interventional radiology (n = 31, 77%), and surgery (n = 8, 87%). Hospital and overall mortality rates were higher in our series (22% and 38%) compared with the published cases (5.3% and 18.4%), respectively (P = 0.02 and P = 0.07). DISCUSSION: A quarter of patients with cirrhosis and SIV experience bleeding, with high transfusion requirements, frequent need for secondary interventions, and high mortality. These findings highlight the need for a multidisciplinary approach and second-line therapeutic modalities in the timely management of bleeding SIV in cirrhosis.

Reproductive Characteristics and Pregnancy Outcomes in Hidden Celiac Disease Autoimmunity.

INTRODUCTION: Untreated symptomatic celiac disease (CD) adversely affects female reproduction; however, the effect of hidden CD autoimmunity is uncertain. METHODS: We identified women who were not previously diagnosed with CD and tested positive for tissue transglutaminase and endomysial antibodies between 2006 and 2011 in a community-based retrospective cohort study. We evaluated (i) the rate of adverse pregnancy outcomes and medical complications of pregnancy in successful singleton deliveries and (ii) reproductive characteristics in seropositive women without a clinical diagnosis of CD and age-matched seronegative women. RESULTS: Among 17,888 women whose serum samples were tested for CD autoimmunity, 215 seropositive and 415 seronegative women were included. We reviewed 231 and 509 live singleton deliveries of 117 seropositive and 250 seronegative mothers, respectively. Menarche and menopausal age, gravidity, parity, and age at first child were similar in seropositive and seronegative women. CD seropositivity was not associated with an increased risk of maternal pregnancy complications. Maternal seropositivity was associated with small for gestational age in boys (OR 3.77, 95% CI: 1.47-9.71; P = 0.006), but not in girls (OR 0.57, 95% CI: 0.15-2.17; P = 0.41). CD serum positivity was not associated with prematurity, small for gestational age (birth weight <10th percentile), or 5-minute Apgar score of less than 7. DISCUSSION: Although underpowered, the present study did not show any difference in reproductive characteristics or rates of adverse pregnancy outcomes in women with and without CD autoimmunity, except for birth weight in male offspring. Larger studies are needed to determine the effects of CD autoimmunity on female reproduction.

Estimating the Impact of Verification Bias on Celiac Disease Testing.

GOAL: The goal of this study was to estimate the impact of verification bias on the diagnostic accuracy of immunoglobulin A tissue transglutaminase (IgA tTG) in detecting celiac disease as reported by an authoritative meta-analysis, the 2016 Comparative Effectiveness Review (CER). BACKGROUND: Verification bias is introduced to diagnostic accuracy studies when screening test results impact the decision to verify disease status. MATERIALS AND METHODS: We adjusted the sensitivity and specificity of IgA tTG reported by the 2016 CER with the proportion of IgA tTG positive and negative individuals who are referred for confirmatory small bowel biopsy. We performed a systematic review from January 1, 2007, to July 19, 2017, to determine these referral rates. RESULTS: The systematic review identified 793 articles of which 9 met inclusion criteria (n=36,477). Overall, 3.6% [95% confidence interval (CI): 1.1%-10.9%] of IgA tTG negative and 79.2.2% (95% CI: 65.0%-88.7%) of IgA tTG positive individuals were referred for biopsy. Adjusting for these referral rates the 2016 CER reported sensitivity of IgA tTG dropped from 92.6% (95% CI: 90.2%-94.5%) to 57.1% (95% CI: 35.4%-76.4%) and the specificity increased from 97.6% (95% CI: 96.3%-98.5%) to 99.6% (95% CI: 98.4%-99.9%). CONCLUSIONS: The CER may have largely overestimated the sensitivity of IgA tTG due to a failure to account for verification bias. These findings suggest caution in the interpretation of a negative IgA tTG to rule out celiac disease in clinical practice. More broadly, they highlight the impact of verification bias on diagnostic accuracy estimates and suggest that studies at risk for this bias be excluded from systematic reviews.

The role of female endoscopists: are women gastroenterologists better at obtaining biopsies for celiac disease than men?

OBJECTIVES: Celiac disease (CD) is commonly found in women. Given the sex differences in diagnosed patients, we hypothesized sex differences in physicians obtaining biopsies for CD may exist. MATERIALS AND METHODS: We retrospectively reviewed duodenal biopsies for suspected CD excluding pre-existing CD patients. Appropriate biopsy practice was defined as ≥5 specimens per ACG guidelines. RESULTS: We included 125 patients (females, 92). There were 85 properly (68%) biopsied. Presence of a female endoscopist was associated with better adherence to biopsy guidelines (OR, 2.99, 95% CI, 1.19-7.54; p = .02) which remained significant after multivariable adjustment (adjusted OR, 2.7; p = .047). CONCLUSIONS: Physician sex-based differences in biopsy patterns may exist.

Histoplasmosis in Inflammatory Bowel Disease with Tumor Necrosis Factor-Alpha Inhibitors: Safe to Continue Biologics?

BACKGROUND: The advent of tumor necrosis factor-α (TNF-α) inhibitor therapy has transformed inflammatory bowel disease management; however, these medications carry a boxed warning for risk of serious infections, including invasive fungal infections. AIMS: We aimed to study the clinical features, severity, and outcomes of histoplasmosis in patients on TNF-α inhibitors for IBD. METHODS: We performed a retrospective review of IBD patients receiving TNF-α inhibitors who developed histoplasmosis from January 1, 2001, to May 31, 2018. Patients with drug indications other than ulcerative colitis or Crohn's disease were excluded. IBD was diagnosed histologically, radiographically, or endoscopically. RESULTS: We identified 49 patients (median age 44 years; range 19-76) with histoplasmosis on TNF-α inhibitors. Patients with disseminated disease had a median urine antigen of 10.76 ng/mL compared with pulmonary disease alone 0.375 ng/mL (p < 0.001). Charlson Comorbidity Index and urine antigen levels showed a trend toward predicting disease severity (p > 0.05). Median length of stay was 9.5 days. Itraconazole was used for maintenance in all patients. Median follow-up was 4.7 years. Total treatment duration ranged from 3 to 15 months. TNF-α inhibitor therapy was continued in nine and resumed in ten patients after completing antifungals. Three deaths occurred (6%). CONCLUSIONS: Histoplasmosis outcomes were mostly favorable. Many patients were young with few comorbidities; however, those with more comorbidities experienced more severe histoplasmosis. Compared to prior studies, many of these patients resumed or continued biologic therapy. There were no histoplasmosis recurrences after resuming TNF-α inhibitor therapy. Vigilance for disseminated fungal infections in this patient population is essential.

High prevalence of food intolerances among US internet users.

OBJECTIVE: Food intolerances are commonly reported and are predicted to have gastrointestinal health implications. We aimed to quantify the prevalence of food intolerances among US adults and identify culprit foods through a brief web-based survey. DESIGN: We invited participation in an online cross-sectional survey involving a single questionnaire. Data were summarised using percentages or medians and interquartile range. Participant characteristics by self-reported food intolerance were compared using the Wilcoxon rank sum test and Pearson's χ2 test. Adjusted analyses were performed using multivariable logistic regression. SETTING: The survey was internet-based via Amazon's mechanical Turk, a crowdsourcing website for the completion of requester directed tasks. PARTICIPANTS: Adults who were US-based internet users were invited at ages 18-80. RESULTS: We collected 2133 survey responses (ages 18-79 years). The rate of food intolerance was 24·8 % (95 % CI 23·0, 26·6) in US adults. Younger (P < 0·01), female (P = 0·05) and Asian, African American or multiple race individuals (P < 0·01) predominated. Lactose intolerance was most common. Frequency of a non-lactose food intolerance was 18·1 % (95 % CI 16·5, 19·8). When categorised broadly, grains, fruit, lactose, fish, vegetables, alcohol and nuts were most troublesome for individuals in that order. CONCLUSIONS: Self-reported food intolerance is common in US internet users. The effect of food on gastrointestinal symptoms and avoidant behaviours deserves further attention.

Sex Difference in Celiac Disease in Undiagnosed Populations: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: A higher proportion of female vs male patients receive a diagnosis of celiac disease. Little is known about sex-based differences in the prevalence of celiac disease in undiagnosed populations. We aimed to address this knowledge gap with a systematic review and meta-analysis. METHODS: We searched MEDLINE, Embase, Cochrane, and Scopus databases through 2017 for studies of screen-detected or undiagnosed celiac disease. Our final analysis included studies that included screening and confirmatory tests (either second serologic analysis or a small intestine biopsy) and provided information on the sex of participants. Studies were excluded if they were performed with specific, high-risk, or referral populations. The primary outcome was the percentage of undetected celiac disease among female and male patients. RESULTS: We identified 4070 articles and analyzed data from 87. Our meta-analysis comprised data from 291,969 study participants. The pooled prevalence of undetected celiac disease in female participants was 0.589% (95% CI, 0.549%-0.629%) and in male participants was 0.415% (95% CI, 0.343%-0.487%). The risk of undetected celiac disease was higher among female than male participants (relative risk [RR], 1.42; 95% CI, 1.27-1.57; P < .00001). The I2 was 5% (low heterogeneity among studies). In subgroup analyses, the RR of celiac disease for girls vs boys was 1.79 (95% CI, 1.44-2.22; P < .00001; I2 = 18%), the RR for female vs male blood donors was 1.13 (95% CI, 0.76-1.69; P = .54; I2 = 0), and the RR for women vs men with villous atrophy was 1.38 (95% CI, 1.07-1.79; P = .01; I2 = 0). CONCLUSIONS: In a systematic review and meta-analysis, we found a higher risk for celiac disease in women than men in an undiagnosed populations (identified through general population screening). The increased risk for celiac disease among girls and women should be considered for screening, diagnosis, and management strategies.

Gender-Based Differences in a Population-Based Cohort with Celiac Disease: More Alike than Unalike.

BACKGROUND: There is a gap in research focused on gender-based differences in non-referral populations with celiac disease. AIMS: The aim of this study was to estimate those differences in a unique population-based cohort of patients with celiac disease with respect to (1) presenting symptoms, (2) associated autoimmune disorders, and (3) survival. METHODS: Clinical data were systematically abstracted from the electronic medical record of a population-based incident cohort of patients with celiac disease. Logistic regression was used to assess the strength of the association of presenting symptoms and gender. Survival differences between genders were evaluated with Cox regression. RESULTS: We included 282 patients (females 65%, median age 39 years) diagnosed between 1990 and 2015. The female to male ratio was 1.85:1. Men and women presented similarly. Women were more likely to present with constipation (OR 2.33; 95% CI 1.06-5.12; p = 0.035). Anemia and abdominal distention or bloating were more frequently seen in women, but not on a statistically significant level. Overall autoimmune diseases were equally prevalent (31.6%) in males (30.2%) and females (32.2%) (p = 0.74). Hypothyroidism predominated in women. Age-adjusted survival was lower among men than women (HR 3.00; 95% CI 1.26-7.21, p = 0.014), but not more so than in the general population. Cancer was the most common cause of death, and there were two possible celiac disease-related deaths. CONCLUSIONS: This study showed that men and women are more alike than unalike when it comes to celiac disease presentation and prevalence of concurrent autoimmune disease.