Preclinical Serological Signatures are Associated With Complicated Crohn's Disease Phenotype at Diagnosis.

BACKGROUND: At diagnosis, up to one-third of patients with Crohn's disease (CD) have a complicated phenotype with stricturing (B2) or penetrating (B3) behavior or require early surgery. We evaluated protein biomarkers and antimicrobial antibodies in serum archived years before CD diagnosis to assess whether complicated diagnoses were associated with a specific serological signature. METHODS: Prediagnosis serum was obtained from 201 patients with CD and 201 healthy controls. Samples were evaluated with a comprehensive panel of 1129 proteomic markers (SomaLogic) and antimicrobial antibodies. CD diagnosis and complications were defined by the International Classification of Diseases-Ninth Revision and Current Procedural Terminology codes. Cox regression models were utilized to assess the association between markers and the subsequent risk of being diagnosed with complicated CD. In addition, biological pathway and network analyses were performed. RESULTS: Forty-seven CD subjects (24%) had a B2 (n = 36) or B3 (n = 9) phenotype or CD-related surgery (n = 2) at diagnosis. Subjects presenting with complicated CD at diagnosis had higher levels of antimicrobial antibodies six years before diagnosis as compared with those diagnosed with noncomplicated CD. Twenty-two protein biomarkers (reflecting inflammatory, fibrosis, and tissue protection markers) were found to be associated with complicated CD. Pathway analysis of the altered protein biomarkers identified higher activation of the innate immune system and complement or coagulation cascades up to six years before diagnosis in complicated CD. CONCLUSIONS: Proteins and antimicrobial antibodies associated with dysregulated innate immunity, excessive adaptive response to microbial antigens, and fibrosis precede and predict a complicated phenotype at the time of diagnosis in CD patients.

Neutralizing Anti-Granulocyte Macrophage-Colony Stimulating Factor Autoantibodies Recognize Post-Translational Glycosylations on Granulocyte Macrophage-Colony Stimulating Factor Years Before Diagnosis and Predict Complicated Crohn's Disease.

BACKGROUND & AIMS: Anti-granulocyte macrophage-colony stimulating factor autoantibodies (aGMAbs) are detected in patients with ileal Crohn's disease (CD). Their induction and mode of action during or before disease are not well understood. We aimed to investigate the underlying mechanisms associated with aGMAb induction, from functional orientation to recognized epitopes, for their impact on intestinal immune homeostasis and use as a predictive biomarker for complicated CD. METHODS: We characterized using enzyme-linked immunosorbent assay naturally occurring aGMAbs in longitudinal serum samples from patients archived before the diagnosis of CD (n = 220) as well as from 400 healthy individuals (matched controls) as part of the US Defense Medical Surveillance System. We used biochemical, cellular, and transcriptional analysis to uncover a mechanism that governs the impaired immune balance in CD mucosa after diagnosis. RESULTS: Neutralizing aGMAbs were found to be specific for post-translational glycosylation on granulocyte macrophage-colony stimulating factor (GM-CSF), detectable years before diagnosis, and associated with complicated CD at presentation. Glycosylation of GM-CSF was altered in patients with CD, and aGMAb affected myeloid homeostasis and promoted group 1 innate lymphoid cells. Perturbations in immune homeostasis preceded the diagnosis in the serum of patients with CD presenting with aGMAb and were detectable in the noninflamed CD mucosa. CONCLUSIONS: Anti-GMAbs predict the diagnosis of complicated CD long before the diagnosis of disease, recognize uniquely glycosylated epitopes, and impair myeloid cell and innate lymphoid cell balance associated with altered intestinal immune homeostasis.

Symptom Outcomes of Celiac Disease in Those on a Gluten-free Diet.

GOALS: We aimed to evaluate symptom outcomes in those on a gluten-free diet during the 5 years after diagnosis. BACKGROUND: Celiac disease is common; however, little is known about long-term symptom outcomes. STUDY: We performed a retrospective chart review on individuals with celiac disease followed at a tertiary referral center between 2012 and 2018. To minimize bias, strict inclusion/exclusion criteria were utilized. Only those with definitive biopsy-proven celiac disease, on a gluten-free diet, and with systematic follow-up were included. The standardized care at this center reduced the risk that decisions on testing and follow-up visits were determined by symptom status. Summary statistics were computed and generalized linear models with a logit link were used to associate the proportion of symptomatic visits with various covariates using R statistical programming. RESULTS: Of the 1023 records reviewed, 212 met inclusion/exclusion criteria; 146 (69%) were female and the mean age at diagnosis was 43 (range: 11 to 84 y old). During follow-up, over 50% remained symptomatic, with many having the same symptoms that prompted the diagnosis. The only predictors for remaining symptomatic were female sex and younger age at diagnosis. Abnormal serology during follow-up and small bowel normalization were not predictive. CONCLUSIONS: In individuals with definitive celiac disease with systematic long-term follow-up in a Celiac Clinic, roughly half remained symptomatic despite a gluten-free diet. Many suffer from the same symptoms that prompted the diagnosis of celiac disease. Small bowel healing and abnormal serology in follow-up were not predictive of remaining symptomatic. These findings stress the importance of long-term care in celiac disease.

Collagenous Gastritis: Characteristics and Response to Topical Budesonide.

BACKGROUND AND AIMS: Collagenous gastritis (CG) is a rare disorder characterized by subepithelial collagen deposition in the stomach. Standard medications have been only moderately successful in treating CG. We report results of a large, retrospective, open-label noncontrolled study of topical budesonide for CG, with an aim of establishing an alternative therapy for the disease. METHODS: We identified patients treated for CG at Mayo Clinic (2000-2017) with topically targeted budesonide (TTB) in 2 formulations: open-capsule budesonide or compounded immediate-release budesonide capsule. Demographic, clinical, biochemical, and histologic variables were assessed for all patients before and after treatment. RESULTS: We identified 64 patients with CG (50 adults, 14 children). Most were female (68%), mean age was 41 ± 22.8 years, and body mass index was 23.1 ± 5.9 kg/m2. In most pediatric patients, CG presented with abdominal pain and anemia; in adults, CG presented more often with weight loss (P < .001). Collagenous sprue or colitis were more common in patients >50 years of age (83%) vs those 19-50 years of age (27%) or <19 years of age (50%) (P < .001). Of the patients treated with TTB, 89% had a clinical response to TTB (42% complete, 46% partial), and 88% had a histologic response (53% complete, 33% partial). CONCLUSIONS: Adults and children with CG have a wide variety of symptoms, and notably, TTB therapy produced clinical and histologic improvement after other therapy had failed.

Plasma IL-2 and Symptoms Response after Acute Gluten Exposure in Subjects With Celiac Disease or Nonceliac Gluten Sensitivity.

INTRODUCTION: Treated patients with celiac disease (CeD) and nonceliac gluten sensitivity (NCGS) report acute, transient, incompletely understood symptoms after suspected gluten exposure. To determine whether (i) blinded gluten exposure induces symptoms, (ii) subjects accurately identify gluten exposure, and (iii) serum interleukin-2 (IL-2) levels distinguish CeD from NCGS subjects after gluten exposure. METHODS: Sixty subjects (n = 20 treated, healed CeD; n = 20 treated NCGS; n = 20 controls) were block randomized to a single, double-blind sham (rice flour) or 3-g gluten challenge with 72-hours follow-up. Twelve serial questionnaires (100 mm visual analog scale; pain, bloating, nausea, and fatigue) and 10 serial plasma samples were collected. Mucosal permeability was assessed using both urinary lactulose-13C mannitol ratios and endoscopic mucosal impedance. RESULTS: Thirty-five of 40 (83%) subjects with CeD and NCGS reported symptoms with gluten (8 CeD, 9 NCGS) and sham (9 CeD, 9 NCGS) compared with 9 of 20 (45%) controls after gluten (n = 6) and sham (n = 3). There was no significant difference in symptoms among groups. Only 2 of 10 subjects with CeD and 4 of 10 NCGS identified gluten, whereas 8 of 10 subjects with CeD and 5 of 10 NCGS identified sham. A significant plasma IL-2 increase occurred only in subjects with CeD after gluten, peaking at 3 hours and normalizing within 24 hours postchallenge despite no significant intestinal permeability change from baseline. DISCUSSION: Symptoms do not reliably indicate gluten exposure in either subjects with CeD or NCGS. IL-2 production indicates a rapid-onset gluten-induced T-cell activation in CeD despite long-standing treatment. The effector site is unknown, given no increased intestinal permeability after gluten.

Administration of Human Derived Upper gut Commensal Prevotella histicola delays the onset of type 1 diabetes in NOD mice.

BACKGROUND: Type 1 diabetes (T1D) is an autoimmune disease that is increasing in prevalence worldwide. One of the contributing factors to the pathogenesis of T1D is the composition of the intestinal microbiota, as has been demonstrated. in T1D patients, with some studies demonstrating a deficiency in their levels of Prevotella. We have isolated a strain of Prevotella histicola from a duodenal biopsy that has anti-inflammatory properties, and in addition, alters the development of autoimmune diseases in mouse models. Therefore, our hypothesis is that the oral administration of P. histicola might delay the development of T1D in the non-obese diabetic (NOD) mice. To assess this, we used the following materials and methods. Female NOD mice (ages 5-8 weeks) were administered every other day P. histicola that was cultured in-house. Blood glucose levels were measured every other week. Mice were sacrificed at various time points for histopathological analysis of the pancreas. Modulation of immune response by the commensal was tested by analyzing regulatory T-cells and NKp46+ cells using flow cytometry and intestinal cytokine mRNA transcript levels using quantitative RT-PCR. For microbial composition, 16 s rRNA gene analysis was conducted on stool samples collected at various time points. RESULTS: Administration of P. histicola in NOD mice delayed the onset of T1D. Beta diversity in the fecal microbiomes demonstrated that the microbial composition of the mice administered P. histicola was different from those that were not treated. Treatment with P. histicola led to a significant increase in regulatory T cells with a concomitant decrease in NKp46+ cells in the pancreatic lymph nodes as compared to the untreated group after 5 weeks of treatment. CONCLUSIONS: These observations suggest that P. histicola treatment delayed onset of diabetes by increasing the levels of regulatory T cells in the pancreatic lymph nodes. This preliminary work supports the rationale that enteral exposure to a non pathogenic commensal P. histicola be tested as a future therapy for T1D.

Celiac Disease: Risk of Hepatitis B Infection.

OBJECTIVE: The aim of our study was to assess the response to hepatitis B virus (HBV) vaccination and the risk of HBV infection in patients with celiac disease (CD). PATIENTS AND METHODS: We performed a cross-sectional study using the National Health and Nutrition Examination Survey (NHANES) database (2009-2014) to assess the rate of HBV vaccination, immune response, and HBV infection risk in patients with and without CD. We also determined the rate of HBV infection via retrospective analysis of two cohorts: patients seen at Mayo Clinic (1998-2021), and a stable longitudinally observed cohort, the Rochester Epidemiology Project (REP; 2010-2020). RESULTS: Based on the NHANES data, the rate of HBV infection in the United States was 0.33% (95% confidence interval 0.25-0.41). Of 93 patients with CD, 46 (49%) were vaccinated for HBV and of the remaining 19,422 without CD, 10,228 (53%) were vaccinated. Twenty-two (48%) vaccinated patients with CD had HBV immunity and 4405 (43.07%) vaccinated patients without CD had HBV immunity, which was not statistically different. In NHANES data, there were no cases of HBV infection in patients with CD. During the study period, 3568 patients with CD were seen at Mayo Clinic and 3918 patients with CD were identified using the REP database. Of those patients with CD, only four (0.11%) at Mayo Clinic and nine (0.23%) of the REP patients had HBV infection. CONCLUSION: The rate of HBV vaccination and immunity was similar in individuals with and without CD. Predictably, no increased risk of HBV infection was detected in CD patients. These results do not support screening and revaccination practice for HBV immunity in patients with CD within the United States.

Community-Based Study of Celiac Disease Autoimmunity Progression in Adults.

BACKGROUND & AIMS: Celiac disease can develop at any age, but outcomes of adults with positive results from serologic tests for tissue transglutaminase antibodies (tTGA) without endoscopic determination of celiac disease (called celiac autoimmunity) have not been thoroughly evaluated. We investigated the proportion of adults with celiac autoimmunity at a community medical center and their progression to celiac disease. METHODS: We analyzed waste blood samples from a community clinic from 15,551 adults for tTGA and, if titer results were above 2 U/mL, for endomysial antibody. The blood samples had been collected at 2 time points (median interval, 8.8 years) from 2006 through 2017. We collected data from the clinic on diagnoses of celiac disease based on duodenal biopsy analysis. RESULTS: Of the serum samples collected at the first time point, 15,398 had negative results for tTGA, and 153 had positive results for tTGA (>4 U/mL). Based on medical records, 6 individuals received a diagnosis of celiac disease, for a cumulative incidence of celiac disease diagnosis of 0.06% (95% confidence interval, 0.01-0.11). Forty-nine (0.32%) individuals with a negative result from the first serologic test for tTGA had a positive result from the second test. Among the 153 adults who were tTGA positive at the first time point, 31 (20%) had a subsequent diagnosis of celiac disease, 81 (53%) remained positive for tTGA without a clinical diagnosis of celiac disease, and 41 (27%) had negative test results for tTGA at the second time point. Higher initial tTGA titers, female sex, and a history of hypothyroidism and autoimmune disease were associated with increased risks of subsequent diagnosis of celiac disease. Interestingly, adults whose first blood sample had a positive test result but second blood sample had a negative result for tTGA were older, had lower-than-average initial tTGA titer results, and had a higher mean body mass index than adults whose blood samples were positive for tTGA at both time points and adults later diagnosed with celiac disease. CONCLUSIONS: In an analysis of serum samples collected from a community clinic an average of 8.8 years apart, we found that fewer than 1% of adults with negative results from an initial test for tTGA have a positive result on a second test. Of adults with positive results from the test for tTGA, only 20% are later diagnosed with celiac disease; the remaining individuals maintain persistent increases in tTGA without diagnoses of celiac disease or have negative results from second tests.

Serum Biomarkers Identify Patients Who Will Develop Inflammatory Bowel Diseases Up to 5 Years Before Diagnosis.

BACKGROUND & AIMS: Biomarkers are needed to identify patients at risk for development of inflammatory bowel diseases. We aimed to identify serum biomarkers of Crohn's disease and ulcerative colitis that can be detected and quantified before diagnosis. METHODS: We obtained serum samples from patients archived before a diagnosis of Crohn's disease (n = 200) or ulcerative colitis (n = 199), as well as from 200 healthy individuals (controls), collected from 1998 through 2013 as part of the US Defense Medical Surveillance System. We measured levels of antibodies against microbes (anti-Saccharomyces cerevisiae IgA or IgG, anti-Escherichiacoli outer membrane porin C, anti-CBir1, anti-flagellin 2, anti-flagellin X, and perinuclear anti-neutrophil cytoplasmic antibodies) and 1129 proteins in each sample. We then used functional principal component analysis to derive the time-varying trajectory for each marker, which then was used in a multivariate model to predict disease status. Predictive performances at different prediagnosis timepoints were evaluated using area under the receiver operating characteristic curves (AUROCs). Biological pathways that were up-regulated in serum from patients with Crohn's disease were identified based on changes in protein abundance at different time periods preceding diagnosis. RESULTS: We identified a panel of 51 protein biomarkers that were predictive of Crohn's disease within 5 years with an AUROC of 0.76 and a diagnosis within 1 year with an AUROC of 0.87. Based on the proteins included in the panel, imminent development of CD was associated with changes in the complement cascade, lysosomes, innate immune response, and glycosaminoglycan metabolism. Serum antibodies and proteins identified patients who received a diagnosis of ulcerative colitis within 5 years with an AUROC of only 0.56 and within 1 year with an AUROC of 0.72. CONCLUSIONS: We identified a panel of serum antibodies and proteins that were predictive of patients who will receive a diagnosis of Crohn's disease within 5 years with high accuracy. By contrast we did not identify biomarkers associated with future diagnosis of ulcerative colitis.

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.

Synthetic Neoepitopes of the Transglutaminase-Deamidated Gliadin Complex as Biomarkers for Diagnosing and Monitoring Celiac Disease.

BACKGROUND & AIMS: Celiac disease (CeD) has characteristics of an autoimmune disease, such as increased antibody levels to tissue transglutaminase (tTG). However, assays to measure these biomarkers in blood samples do not identify patients with sufficient accuracy for diagnosis or monitoring of CeD. We aimed to discover biomarkers of CeD derived from neoepitopes of deamidated gliadin peptides (DGP) and tTG fragments and to determine if immune reactivity against these epitopes can identify patients with CeD with mucosal healing. METHODS: We analyzed serum samples from 90 patients with biopsy-proven CeD and 79 healthy individuals (controls) for immune reactivity against the tTG-DGP complex (discovery cohort). A fluorescent peptide microarray platform was used to estimate the antibody-binding intensity of each synthesized tTG-DGP epitope. We validated our findings in 82 patients with newly diagnosed CeD and 217 controls. We tested the ability of our peptide panel to identify patients with mucosal healing (based on the histologic analysis) using serum samples from patients with treated and healed CeD (n = 85), patients with treated but unhealed CeD (n = 81; villous atrophy despite a adhering a gluten-free diet), patients with untreated CeD (n = 82) and disease controls (n = 27), villous atrophy without CeD), and healthy controls (n = 217). Data were analyzed using principal component analysis followed by machine learning and support vector machine modeling. RESULTS: We identified 172 immunogenic epitopes of the tTG-DGP complex. We found significantly increased immune reactivity against these epitopes vs controls. In the both cohort, the set of neoepitopes derived from the tTG-DGP complex identified patients with CeD with 99% sensitivity and 100% specificity. Serum samples from patients with untreated CeD had the greatest mean antibody-binding intensity against the tTG-DGP complex (32.5 ± 16.4). The average antibody-binding intensity was significantly higher in serum from patients with treated but unhealed CeD mucosa (15.1 ± 7.5) than in patients with treated and healed CeD mucosa (5.5 ± 3.4) (P < .001). The assay identified patients with mucosa healing status with 84% sensitivity and 95% specificity. CONCLUSIONS: We identified immunogenic epitopes of the tTG-DGP complex, and found that an assay to measure the immune response to epitopes accurately identified patients with CeD, as well as patients with mucosal healing. This biomarker assay might be used in detection and monitoring of patients with CeD.

Effect of a Gluten-free Diet on Quality of Life in Patients With Nonclassical Versus Classical Presentations of Celiac Disease.

BACKGROUND: Celiac disease (CD) often presents with symptoms of diarrhea and malabsorption, termed classical CD. However, it can also present as nonclassical CD, which is commonly associated with nongastrointestinal symptoms. Studies suggest that nonclassical CD tends to have less severe symptoms than classical CD, which may affect both adherence to a gluten-free diet (GFD) and psychological stress. Therefore, we compared adherence to a GFD and psychological measures, including quality of life (QOL) and somatization, between patients with nonclassical and classical presentations of CD. METHODS: Patients at a tertiary care center with biopsy-proven CD, who completed a Talley Bowel Disease Questionnaire and the Short Form-36 at diagnosis and who had been on a GFD for at least 1 year, were included in this study. Patients were further surveyed to assess gastrointestinal symptoms, QOL, Somatization Symptom Checklist (SSC), and adherence to a GFD. Results were compared between patients with classical versus nonclassical CD presentation. RESULTS: Among 122 patients included in this study, 62 had classical CD and 60 had nonclassical CD. At diagnosis, health-related QOL was lower in the classical CD group than in the nonclassical CD group. After following a GFD, both groups had improved QOL after following a GFD, and body mass index significantly increased in both groups. Most subscales of QOL, SSC scores, and adherence to the GFD were similar between the groups, except the Short Form-36 Mental Component summary scores that were still lower in the classical CD (48.4 vs. 52.6 nonclassical CD group; P=0.03). CONCLUSIONS: Despite QOL at diagnosis being higher in those with nonclassical CD versus lower in those with classical CD, both groups had improved QOL and achieved a similar QOL after following a GFD.

Autoimmune and Allergic Disorders are More Common in People With Celiac Disease or on a Gluten-free Diet in the United States.

GOALS: We analyzed demographics, lifestyle patterns, and clinical characteristics of people with celiac disease (CD) and people without CD avoiding gluten (PWAG) to better understand associations with medical conditions and consumer behavior. BACKGROUND: Clinical significance of CD and gluten avoidance in the general population is incompletely understood. Recently, a high incidence of CD in adolescents with susceptibility genotypes, similar to other autoimmune or allergic disorders, and regional differences in consumer practices of gluten avoidance were reported. METHODS: Among 22,277 participants in the National Health and Nutrition Examination Survey 2009-2014, we identified persons with CD by testing CD serology or by both a health care provider diagnosis and adherence to a gluten-free diet. Similarly, PWAG were defined as adherent to a gluten-free diet without a CD diagnosis. Consumer behavior and characteristics of both groups, CD and PWAG were compared with those without these conditions, using survey-weighted generalized logistic regression. RESULTS: Participants with CD considered nutrition very important when grocery shopping and tended to have more constipation and thyroid disease. PWAG tended to spend more money on groceries, purchase organic foods, and check food labels more frequently during grocery shopping. They also reported having more food allergies, asthma, and thyroid disease. CONCLUSIONS: Our study confirms that CD and PWAG share comorbidities of autoimmune nature. PWAG had more autoimmune/allergy-related disorders that may be associated with non-celiac gluten sensitivity a self-justifiable reason to be on the diet.

Lower Prevalence of Celiac Disease and Gluten-Related Disorders in Persons Living in Southern vs Northern Latitudes of the United States.

BACKGROUND & AIMS: The association between prevalence of celiac disease and geographic region is incompletely understood, but the occurrence of several autoimmune disorders has been found to vary along a North-South gradient. We examined geographic, demographic, and clinical factors associated with prevalence of celiac disease and gluten-free diet in the United States. METHODS: In a population-based study, we analyzed data on gluten-related conditions from the National Health and Nutrition Examination Survey, from 2009 through 2014, on 22,277 participants 6 years and older. We identified persons with celiac disease based on results of serum tests for IgA against tissue transglutaminase and endomysium or on both a health care provider diagnosis and adherence to a gluten-free diet. Gluten avoidance without celiac disease was defined as adherence to a gluten-free diet without a diagnosis of celiac disease. We compared mean serum levels of biochemical and nutritional markers based on status of gluten-related conditions. RESULTS: We found 0.7% of participants to have celiac disease and 1.1% of participants to avoid gluten without celiac disease. Celiac disease was more common among individuals who lived at latitudes of 35°-39° North (odds ratio, 3.2; 95% confidence interval, 1.4-7.1) or at latitudes of 40° North or more (odds ratio, 5.4; 95% CI, 2.6-11.3) than individuals who lived at latitudes below 35° North, independent of race or ethnicity, socioeconomic status, and body mass index. Gluten avoidance without celiac disease was more common among individuals who lived at latitudes of 40° North or more, independent of demographic factors and body mass index. Participants with undiagnosed celiac disease (identified by positive results from serologic tests) had lower mean levels of vitamin B-12 and folate (data collected from 2009 through 2012) than persons without celiac disease. Participants with a health care provider diagnosis of celiac disease had a lower mean level of hemoglobin than persons without celiac disease. Mean levels of albumin, calcium, iron, ferritin, cholesterol, vitamin B-6, and vitamin D (data collected from 2009 through 2010) did not differ between participants with gluten-related conditions and those without. CONCLUSIONS: In the US population, a higher proportion of persons living at latitudes of 35° North or greater have celiac disease or avoid gluten than persons living south of this latitude, independent of race or ethnicity, socioeconomic status, or body mass index. Mean levels of vitamin B-12 and folate are lower in individuals with undiagnosed celiac disease, and levels of hemoglobin are lower in participants with a diagnosis of celiac disease, compared with individuals without celiac disease.

Accumulation of Heavy Metals in People on a Gluten-Free Diet.

BACKGROUND & AIMS: Specific foods such as fish and rice have high concentrations of metals such as arsenic, mercury, lead, cadmium, and cobalt. Many gluten-free diets (GFDs) include these foods, so we evaluated whether a GFD was associated with increased metal bioaccumulation. METHODS: We performed a population-based, cross-sectional study using data collected from the National Health and Nutrition Examination Survey (NHANES), from 2009 through 2012, collecting information on the diagnosis of celiac disease and adherence to a GFD. We tested NHANES blood samples to identify individuals with undiagnosed celiac disease, using assays for immunoglobulin A tissue transglutaminase followed by a confirmatory test for endomysial antibody. Among a total of 11,354 NHANES participants, celiac disease was diagnosed in 55 participants, based on test results or a reported clinical diagnosis. We collected NHANES survey data on blood levels of lead, mercury, and cadmium from subjects who were on a GFD (n = 115) and participants who were not on a GFD (n = 11,239). Levels of total arsenic in urine samples were available from 3901 subjects not following a GFD and 32 individuals following a GFD. NHANES participants were asked questions about fish and shellfish consumption. We performed multivariate logistic regression analyses to associate gluten-related conditions with blood concentrations of mercury, cadmium, and lead and urine concentration of total arsenic, adjusting for demographic characteristics, as well as for rice consumption or seafood intake. Geometric means were reported for urinary concentrations of total arsenic and blood concentrations of mercury, cadmium, and lead for demographic groups and subjects with gluten-related conditions (subjects without celiac disease who avoid gluten). RESULTS: Persons following a GFD had significantly increased total blood mercury levels (1.37 mcg/L) compared with persons not on a GFD (0.93 mcg/L) (P = .008), as well as increased blood levels of lead (1.42 vs 1.13 mcg/L; P = .007) and cadmium (0.42 vs 0.34 mcg/L; P = .03). Urine samples from subjects on a GFD had higher concentrations of total arsenic (15.15 mcg/L) than urine samples from subjects not on a GFD (8.38 mcg/L) (P = .002). After controlling for demographic characteristics, levels of all heavy metals remained significantly higher in persons following a GFD, compared with those not following a GFD. After exclusion of persons with celiac disease, people without celiac disease on a GFD (n = 101) had significantly increased blood concentrations of total mercury (1.40 mcg/L) than persons without celiac disease and not on a GFD (n = 10,890) (0.93 mcg/L; P = .02) and higher blood concentrations of lead (1.44 vs 1.13 mcg/L; P = .01) and higher urine concentrations of total arsenic (14.69 mcg/L [n = 3632] vs 8.32 mcg/L [n = 28]; P = .01). Blood samples from persons without celiac disease avoiding gluten had higher levels of cadmium (0.42 mcg/L) than persons without celiac disease and not following a GFD (0.34 mcg/L), but this difference was not significant (P = .06). CONCLUSIONS: In an analysis of data collected from NHANES, persons on a GFD had significantly higher urine levels of total arsenic and blood levels of mercury, lead, and cadmium than persons not avoiding gluten. Studies are needed to determine the long-term effects of accumulation of these elements in persons on a GFD.

Features of Adult Autoimmune Enteropathy Compared With Refractory Celiac Disease.

BACKGROUND & AIMS: Little is known about the features of immune-mediated non-celiac villous atrophies, such as autoimmune enteropathy (AIE). We investigated the demographic, clinical, and histologic features of adults with AIE compared to adults with refractory celiac disease type 1. We also report outcomes of treatment with open-label budesonide. METHODS: We performed a retrospective case-control of patients with AIE (n = 30) seen at the Mayo Clinic (in Rochester, Minnesota) from 2000 through 2015. Patients with refractory celiac disease type 1 who were treated with open-label budesonide served as controls (n = 42). Biopsy specimens were reviewed for all patients. We collected demographic, clinical, biochemical and histologic data from patients. We also collected data on responses to open-capsule budesonide from patients with AIE (available from 22 patients) and controls (available from 42 patients); the median duration of follow up was 28 months (range, 0-1421 months). RESULTS: Patients with AIE had a higher proportion of men (60%) and were younger (mean, 44 ± 18 years) than patients with refractory celiac disease type 1 (29% men; P = .002 and mean age, 57 ± 16 years; P = .007). A higher proportion of patients with AIE presented with chronic diarrhea (100%) and weight loss (90%) than patients with refractory celiac disease type 1 (71%; P < .001 and 71%; P = .05, respectively). Based on histologic analysis, there was no significant difference in degree of villous atrophy in intestinal tissues from patients with AIE vs controls (P = .68). However, a greater proportion of patients with RCD had increased intraepithelial lymphocytes (>40 per 100 epithelial cells in 100%) compared with patients with AIE (in 50%) (P = .003). Conventional therapy (systemic steroids) had failed in most patients with AIE (a complete clinical response was reported in only 7 patients) before treatment with open-capsule budesonide was initiated. A clinical response to open-capsule budesonide was reported for 85% of patients with AIE (50% complete response, 35% partial response) compared to 92% of controls (68% complete response, 24% partial response). CONCLUSIONS: In a retrospective study of 30 patients with AIE, followed for a median 28 months, we found this disease to have has distinct demographic, clinical, and histologic characteristics compared to refractory celiac disease type 1. Most patients with AIE (85%) have a clinical response to budesonide, all of whom were unsuccessfully treated with conventional therapies.

Prevalence and Morbidity of Undiagnosed Celiac Disease From a Community-Based Study.

BACKGROUND & AIMS: Little is known about the prevalence and burden of undiagnosed celiac disease in individuals younger than age 50. We determined the prevalence and morbidity of undiagnosed celiac disease in individuals younger than age 50 in a community. METHODS: We tested sera from 31,255 residents of Olmsted County, Minnesota (<50 y), without a prior diagnosis of celiac disease assay using an assay for IgA against tissue transglutaminase; in subjects with positive test results, celiac disease was confirmed using an assay for endomysial IgA. We performed a nested case-control study to compare the proportion of comorbidities between undiagnosed cases of celiac disease and age- and sex-matched seronegative controls (1:2). Medical records were abstracted to identify potential comorbidities. RESULTS: We identified 338 of 30,425 adults with positive results from both serologic tests. Based on this finding, we estimated the prevalence of celiac disease to be 1.1% (95% confidence interval, 1.0%-1.2%); 8 of 830 children tested positive for IgA against tissue transglutaminase (1.0%; 95% confidence interval, 0.4%-1.9%). No typical symptoms or classic consequences of diagnosed celiac disease (diarrhea, anemia, or fracture) were associated with undiagnosed celiac disease. Undiagnosed celiac disease was associated with increased rates of hypothyroidism (odds ratio, 2.2; P < .01) and a lower than average cholesterol level (P = .03) and ferritin level (P = .01). During a median follow-up period of 6.3 years, the cumulative incidence of a subsequent diagnosis with celiac disease at 5 years after testing was 10.8% in persons with undiagnosed celiac disease vs 0.1% in seronegative persons (P < .01). Celiac disease status was not associated with overall survival. CONCLUSIONS: Based on serologic tests of a community population for celiac disease, we estimated the prevalence of undiagnosed celiac disease to be 1.1%. Undiagnosed celiac disease appeared to be clinically silent and remained undetected, but long-term outcomes have not been determined.

Increased risk of herpes zoster in patients with coeliac disease - nationwide cohort study.

BACKGROUND AND AIMS: Clinical experience suggests that patients with coeliac disease (CD) are more prone to develop herpes zoster (HZ), but robust studies are lacking. METHODS: We identified 29,064 patients with CD 1969-2008 using biopsy report data from Sweden's 28 pathology departments. CD was equalled to villous atrophy (Marsh histopathology grade III). Each patient was matched on age, sex, calendar year and county of residence to up to five reference individuals ( n=144,342) from the general population. We then used Cox regression to estimate hazard ratios (HRs) for future HZ (defined as having a hospital-based inpatient or outpatient record of this diagnosis in the Swedish Patient Register). RESULTS: During follow-up, 154 (0.53%) individuals with CD and 499 (0.35%) reference individuals developed HZ. Among individuals aged ≥60 years, 1.06% of CD individuals and 0.85% of reference individuals had a lifetime record of HZ. Overall, CD was associated with a 1.62-fold increased risk of HZ (95% CI=1.35-1.95), and was seen also when we considered comorbidity with lymphoproliferative disease, systemic lupus erythematosus, type 1 diabetes, thyroid disease, rheumatoid disease and excluded individuals with a record of dermatitis herpetiformis. The increased risk remained significant after more than five years of follow-up (1.46; 1.16-1.84) Conclusions: CD is associated with HZ, the increased relative risk persists over time from celiac diagnosis but the absolute risk is small.

Analysis of Biopsies From Duodenal Bulbs of All Endoscopy Patients Increases Detection of Abnormalities but has a Minimal Effect on Diagnosis of Celiac Disease.

BACKGROUND & AIMS: In patients with positive results from serologic tests for celiac disease, analysis of tissues samples from the duodenal bulb, in addition to those from other parts of the small bowel, might increase the diagnostic yield. However, biopsies are not routinely collected from the duodenal bulb because of concerns that villous atrophy detected there could be caused by other disorders (Brunner glands or peptic duodenitis, gastric metaplasia, shorter villi, or lymphoid follicles). We investigated whether analysis of biopsies from duodenal bulbs of all patients undergoing endoscopy (a population with a low probability for celiac disease) increases diagnoses of celiac disease. METHODS: We performed a retrospective analysis of data from 679 patients (63% female; mean age, 50 years) from whom duodenal bulb and small bowel biopsies were collected during endoscopy at 3 Mayo Clinic sites, from January 1, 2011 through December 31, 2011. Records were reviewed for age, sex, pathology findings, serology test results (HLA DQ2 or DQ), indications for biopsy analyses, and adherence to a gluten-free diet. Patients with celiac disease were identified on the basis of increased intraepithelial lymphocytosis, with or without villous atrophy and crypt hyperplasia, and results from serology tests. Findings from duodenal bulbs were compared with diagnoses using the Fisher exact test. RESULTS: Of all patients undergoing endoscopy, 16 patients (2%) were found to have celiac disease. Analysis of the duodenal bulb biopsies identified 1 patient (0.1%) with celiac disease limited to this region. Of 399 patients whose celiac serology was not known before endoscopic examination, only 2 patients had histologic changes consistent with celiac disease but not limited to duodenal bulb. Abnormal duodenal histology was detected in 265 patients (39%), most commonly in the bulb (n = 241; P < .0001). Of abnormal bulb histologies, chronic peptic duodenitis was most common (observed in 114 patients, 47%). In patients with a normal distal duodenum (n = 576), the duodenal bulb had abnormal histology in 162 (28%). CONCLUSIONS: In a low pretest probability cohort, separate sampling of the duodenal bulb had minimal effect on celiac disease detection. Abnormal histologic findings are more commonly detected in the duodenal bulb; although they do not seem to impair identification of celiac disease, their clinical implications are unclear.